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AU2010302648A1 - Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors - Google Patents

Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors Download PDF

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Publication number
AU2010302648A1
AU2010302648A1 AU2010302648A AU2010302648A AU2010302648A1 AU 2010302648 A1 AU2010302648 A1 AU 2010302648A1 AU 2010302648 A AU2010302648 A AU 2010302648A AU 2010302648 A AU2010302648 A AU 2010302648A AU 2010302648 A1 AU2010302648 A1 AU 2010302648A1
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methyl
nrcrc
methoxy
orc
pyrimidin
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AU2010302648A
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Ioannis Sapountzis
Heinz Stadtmueller
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention encompasses compounds of general formulae (1a) and (1b), wherein the groups R to R, A, Q, m, n, p and q are defined as in claim 1, which are FAK/PTK2 inhibitors and thus suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use as medicaments.

Description

WO 2011/039344 PCT/EP2010/064628 PYRIMIDINE DERIVATIVES AS PROTEIN TYROSINE KINASE 2 INHIBITORS The present invention relates to new pyrimidines of general formulae (1a) and (1b) R R 3 R R 3 O O _ N.%N (fl Q 4N-. N R 5 ), & (R 4)m"( HN R2 HN a R 2 (1a) (1 b) wherein the groups R' to R 5 , A, Q, m, n, p and q have the meanings given in the claims 5 and specification, the isomers thereof, processes for preparing these pyrimidines and their use as medicaments. Background to the invention Tumour cells that acquire the properties for invasion and metastasisation require specific survival signals. These signals allow them to overcome special apoptosis mechanisms 10 (anoikis) which are triggered, inter a/ia, by the loss of cell adhesion. In this process, focal adhesion kinase (FAK/PTK2) is one of the essential signal molecules which on the one hand controls cell-matrix interactions through so-called 'focal adhesions' and on the other hand imparts anoikis resistance. Interference with these mechanisms by inhibiting PTK2 may lead to the apoptotic cell death of tumour cells and limit the invasive and 15 metastasising growth of tumours. In addition, focal adhesion kinase has major significance for the growth, migration and survival of tumour-associated endothelial cells. An anti-angiogenic activity may therefore also be achieved by inhibiting PTK2. Pyrimidines are generally known as inhibitors of kinases. Thus, for example, pyrimidines 20 are described as aurora-kinase inhibitors in International Patent Application WO 2008/038011, these pyridines having, as substituents, an oxymethylpiperidinyl group in the 4 position and fluorine in the 5 position. -1- WO 2011/039344 PCT/EP2010/064628 The aim of the present invention is to indicate new pyrimidines as active substances which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation. A further aim of the present invention is to indicate pyrimidines which have an inhibitory effect on the enzyme PTK2 in vitro and/or in 5 vivo and have suitable pharmacological and/or pharmacokinetic properties to enable them to be used as medicaments. These properties include inter alia a selective inhibitory effect on PTK2 in relation to other known cell cycle and signal kinases. Detailed description of the invention It has now been found that, surprisingly, compounds of general formulae (1a) and (1b), 10 wherein the groups R 1 to R 5 , A, Q, m, n, p and q have the meanings given hereinafter act as inhibitors of specific tyrosine-kinases. Thus the compounds according to the invention may be used for example for the treatment of diseases connected to the activity of specific tyrosine-kinases and characterised by excessive or abnormal cell proliferation. The present invention relates to compounds of general formulae (1 a) and (1 b) R R 3 R R 3 N ( R 4) N-! N (q R 5 ) HN , R2 HN ,R2 15 (1a) (1 b) wherein A denotes a group, optionally substituted by one or more, identical or different R 2 , selected from among C 3
-
1 ocycloalkyl, 3-8 membered heterocycloalkyl, C 6 -1 5 aryl and 5-12 membered heteroaryl; 20 Q denotes a group, optionally substituted by one or more, identical or different R 4 , selected from among phenyl and 5-6 membered heteroaryl;
R
1 denotes a group selected from among halogen, -ORc, -OCF 3 , -SRc, -NRcRc, -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , C1- 3 alkyl, C1- 3 haloalkyl and C1- 3 haloalkyloxy; -2- WO 2011/039344 PCT/EP2010/064628
R
2 , R 4 and R 5 each independently of one another denote hydrogen or a group selected from among Ra, Rb and Ra substituted by one or more, identical or different RC and/or Rb;
R
3 denotes a group selected from among -OS(O)Rc, -OS(O) 2 Rc, -OS(O) 2 ORc, -OS(O)NRcRc, -OS(O) 2 NRcRc, -OC(O)Rc, -OC(O)ORc, -OC(O)SRc, -OC(O)NRcRc, 5 -SC(O)Rc, -SC(O)ORc, -SC(O)NRcRc, -N(Rg)C(O)Rc, -N[C(O)Rc] 2 , -N(OR9)C(O)Rc, -N[C(O)Rc]NRcRc, -N(Rg)S(O)Rc, -N(Rg)S(O)ORc, -N(Rg)S(O)2Rc, -N[S(O)2Rc]2 -N(Rg)S(O)2ORc, -N(Rg)S(O)2NRcRc, -N(Rg)[S(O)2]2Rc, -N(Rg)C(O)ORc, -N(Rg)C(O)SRc, -N(Rg)C(O)NRcRc, -N(Rg)C(O)NRgNRcRc, -[N(Rg)C(O)]2Rc, -N(Rg)[C(O)]2Rc, -N{[C(O)]2Rcj2 -N(Rg)[C(O)]2ORc, -N(Rg)[C(O)]2NRcRc, -N{[C(O)] 2 ORc} 2 , -N{[C(O)] 2 NRcRc} 2 and 10 -[N(Rg)C(O)]2ORc; each Ra is independently selected from among C 1
.
6 alky I , C 3
-
1 ocycloalkyl,
C
4
.
1 6 cycloalkylalkyl, C 6
.
1 oaryl, C 7
.
1 6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl; 15 each Rb is a suitable group and each is independently selected from among =0, -ORc,
C
1
-
3 haloalkyloxy, -OCF 3 , =S, -SRc, =NRc, =NORc, =NNRRc, =NN(Rg)C(O)NRcRc, -NRcRc, -ONRcRc, -N(ORc)Rc, -N(Rg)NRcRc, halogen, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 ,
=N
2 , -N 3 , -S(O)Rc, -S(O)ORc, -S(O) 2 Rc, -S(O) 2 ORc, -S(O)NRcRc, -S(O) 2 NRcRc, -OS(O)Rc,
-OS(O)
2 Rc, -OS(O) 2 ORc, -OS(O)NRcRc, -OS(O) 2 NRcRc, -C(O)Rc, -C(O)ORc, -C(O)SRc, 20 -C(O)NRcRc, -C(O)N(Rg)NRcRc, -C(O)N(Rg)ORc, -C(NR9)NRcRc, -C(NOH)Rc, -C(NOH)NRcRc, -OC(O)Rc, -OC(O)ORc, -OC(O)SRc, -OC(O)NRcRc, -OC(NR9)NRcRc, -SC(O)Rc, -SC(O)ORc, -SC(O)NRcRc, -SC(NR9)NRcRc, -N(Rg)C(O)Rc, -N[C(O)Rc]2 -N(OR)C(O)Rc, -N(R)C(NR9)R, -N(Rg)N(Rg)C(O)Rc, -N[C(O)Rc]NRR , -N(Rg)C(S)R , -N(Rg)S(O)R, - N (R g)S(O)OR a, -N(R)S(O)2Re, -N[S(O)2R]2, -N(R)S(O)2ORc, 25 -N(Rg)S(O)2NRcRc, -N(Rg)[S(O)2]2Rc, -N(Rg)C(O)ORc, -N(Rg)C(O)SRc, -N(Rg)C(O)NR3R-, -N(Rg)C(O)NRgNRcRc, -N(Rg)N(Rg)C(O)NRcRc, -N(Rg)C(S)NRcRc, -[N(Rg)C(O)]2Rc, -N(Rg)[C(O)]2Rc, -N{[C(O)]2Rc}2, -N(Rg)[C(O)]2ORc, -N(Rg)[C(O)]2NRcRc, -N{[C(O)]2ORcj2 -N{[C(O)]2NRcRc}2, -[N(Rg)C(O)]2ORc, -N(Rg)C(NR9)ORc, -N(Rg)C(NOH)Rc, -N(Rg)C(NR9)SRc and -N(Rg)C(NR9)NRcRc; 30 each R' independently denotes hydrogen or a group optionally substituted by one or more, identical or different R d and/or R* selected from among C1.salkyl, C3-1ocycloalkyl, C4.11cycloalkylalkyl, C6.1oaryl, Cr.16arylalkyl, 2-6 membered heteroalkyl, 3-8 membered -3- WO 2011/039344 PCT/EP2010/064628 heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl; each Rd is a suitable group and each is independently selected from among =0, -ORe,
C
1
-
3 haloalkyloxy, -OCF 3 , =S, -SRe, =NRe, =NORe, =NNReRe, =NN(Rg)C(O)NRR, -NReRe, 5 -ONReRe, -N(Rg)NReRe, halogen, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)Re, -S(O)ORe, -S(O) 2 Re, -S(O) 2 ORe, -S(O)NReRe, -S(O) 2 NReRe, -OS(O)Re,
-OS(O)
2 Re, -OS(O) 2 ORe, -OS(O)NReRe, -OS(O) 2 NReRe, -C(O)Re, -C(O)ORe, -C(O)SRe, -C(O)NReRe, -C(O)N(Rg)NReRe, -C(O)N(Rg)ORe, -C(NR9)NReRe, -C(NOH)Re, -C(NOH)NReRe, -OC(O)Re, -OC(O)ORe, -OC(O)SRe, -OC(O)NReRe, -OC(NR9)NReR, 10 -SC(O)R e, -SC(O)OR e, -SC(O)NR eR e, -SC(NR9)NR eR e, -N(Rg)C(O)R e, -N[C(O)R e 2 -N(OR9)C(O)Re, -N(Rg)C(NR9)Re, -N(Rg)N(Rg)C(O)Re, -N[C(O)Re]NReRe, -N(Rg)C(S)Re, -N(Rg)S(O)Re, -N(Rg)S(O)ORe, -N(Rg)S(O)2Re, -N[S(O)2Re]2, -N(Rg)S(O)2ORe, -N(R)S(O)2NR R, -N(R)[S(O)2]2Ra , -N(R9)C(O)OR e-N(R)C(O)SR, -N(Rg)C(O)NRR, -N(Rg)C(O)NRgNR Re, -N(Rg)N(Rg)C(O)NReRe, -N(Rg)C(S)NReRe, -[N(Rg)C(O)]2Re, 15 -N(Rg)[C(O)]2R e, -N{[C(O)]2Re}12, -N(Rg)[C(O)]2OR e, -N(Rg)[C(O)]2NR eR e, -N{[C(O)]2OR e12 -N{[C(O)]2NR Re}2, -[N(Rg)C(O)]2ORe, -N(Rg)C(NR9)ORe, -N(Rg)C(NOH)Re, -N(Rg)C(NR9)SR e and -N(Rg)C(NR9)NR eR e; each R* independently denotes hydrogen or a group optionally substituted by one or more, identical or different Rf and/or R9 selected from among C1.salkyl, C3-scycloalkyl, 20 C4.
11 cycloalkylalkyl, C 6
.
1 0 aryl, C 7 16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl; each Rf is a suitable group and each is independently selected from among halogen and
-CF
3 ; 25 each R9 independently denotes hydrogen, C1.
6 alkyl, C3- 8 cycloalkyl, C4.
11 cycloalkylalkyl,
C
6
.
1 oaryl, C 7 1 6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered heteroarylalkyl; m and p independently of one another denote 0, 1, 2 or 3 and 30 n and q denote 0, 1, 2 or 3; -4- WO 2011/039344 PCT/EP2010/064628 optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the salts thereof, particularly the pharmacologically acceptable acid addition salts thereof. In a preferred embodiment the present invention relates to compounds of general formula 5 (1a), R R 3 (RR N z!,N ( Q
(R
4 )m HNa R2 (1a) wherein R', R 2 , R 3 , R 4 , A, Q, n and m are as hereinbefore defined. In another preferred embodiment (Al) the present invention relates to compounds of 10 general formula (1a), wherein n is 1. In another preferred embodiment (A2) the present invention relates to compounds of general formula (1a), wherein the group R 3 and the group R N-, N 15 HNa R2 assume a trans configuration with respect to the ring system to which they bind. In another preferred embodiment (B1) the present invention relates to compounds of general formula (1a), wherein -5- WO 2011/039344 PCT/EP2010/064628 Q is phenyl and
R
4 and m are as hereinbefore defined. In another preferred embodiment (B2) the present invention relates to compounds of general formula (1a), wherein 5 m is 0. In another preferred embodiment the present invention relates to compounds of general formula (1b), R R 3 zYN O q (RE HN 2 (1 b) wherein 10 R 1 , R 2 , R 3 , R , A, p and q are as hereinbefore defined. In another preferred embodiment (A3) the present invention relates to compounds of general formula (1b), wherein q is equal to 1 or 2. In another preferred embodiment (A4) the present invention relates to compounds of 15 general formula (1b), wherein the group R 3 and the group R N-, N HNa R2 assume a trans configuration with respect to the ring system to which they bind. -6- WO 2011/039344 PCT/EP2010/064628 In another preferred embodiment (B3) the present invention relates to compounds of general formula (1b), wherein p is equal to 0. In another preferred embodiment (C1) the present invention relates to compounds of 5 general formulae (1a) and (1b), wherein
R
1 is a group selected from among halogen, -CF 3 , -CN, C 1
-
3 alkyl and C 1
-
3 haloalkyl. In another preferred embodiment (C2) the present invention relates to compounds of general formulae (1a) and (1b), wherein
R
1 is a group selected from among halogen and -CF 3 . 10 In another preferred embodiment (C3) the present invention relates to compounds of general formulae (1a) and (1b), wherein
R
1 denotes -CF 3 . In another preferred embodiment (C4) the present invention relates to compounds of general formulae (1a) and (1b), wherein 15 R 1 denotes chlorine. In another preferred embodiment (D1) the present invention relates to compounds of general formulae (1a) and (1b), wherein
R
3 is a group selected from among -N(Rg)C(O)Rc, -N[C(O)Rc] 2 , -N(OR9)C(O)Rc, -N[C(O)Rc]NRcRc, -N(Rg)S(O)Rc, -N(Rg)S(O)ORc, -N(Rg)S(O)2Rc, -N[S(O)2RCh2 20 -N(Rg)S(O)2ORc, -N(Rg)S(O)2NRcRc, -N(Rg)[S(O)2]2Rc, -N(Rg)C(O)ORc, -N(Rg)C(O)SRc, -N(Rg)C(O)NRcRc, -N(Rg)C(O)NRgNRcRc, -[N(Rg)C(O)]2Rc, -N(Rg)[C(O)]2Rc, -N{[C(O)]2RCj2 -N(Rg)[C(O)]2ORc, -N(Rg)[C(O)]2NRcRc, -N{[C(O)] 2 ORc} 2 , -N{[C(O)] 2 NRcR} 2 , and -[N(Rg)C(O)]20Rc and Rc and R9 are as hereinbefore defined. 25 In another preferred embodiment (D2) the present invention relates to compounds of general formulae (1a) and (1b), wherein -7- WO 2011/039344 PCT/EP2010/064628
R
3 is selected from among -N(Rg)C(O)Rc, -N(OR9)C(O)Rc, -N(Rg)S(O)2Rc, -N(Rg)C(O)ORc and -N(Rg)C(O)NRcRc and RC and R9 are as hereinbefore defined. In another preferred embodiment (D3) the present invention relates to compounds of 5 general formulae (1a) and (1b), wherein
R
3 is selected from among -N(Rg)C(O)Rc, -N(Rg)S(O)2Rc and -N(Rg)C(O)ORc and RC and R9 are as hereinbefore defined. In another preferred embodiment (D4) the present invention relates to compounds of general formulae (1a) and (1b), wherein 10 R 3 is selected from among -N(Rg)C(O)Rcl and -N(Rg)S(O)2Rcl Rc" corresponds to the group RC and RC and R9 are as hereinbefore defined. In another preferred embodiment (D5) the present invention relates to compounds of general formulae (1a) and (1b), wherein 15 R 3 is selected from among -NHC(O)Rcl, -N(C1.
4 alkyl)C(O)Rc1, -NHS(O) 2 Rcl and -N(C1.
4 alkyl)S(O) 2 Rc1; Rc corresponds to the group RC and RC is as hereinbefore defined. In another preferred embodiment (D6) the present invention relates to compounds of 20 general formulae (1a) and (1b), wherein
R
3 is selected from among -NHC(O)Rcl, -N(Me)C(O)Rcl, -N(Et)C(O)Rcl, -N(iPr)C(O)Rcl, -N(nPr)C(O)Rcl, -NHS(O) 2 Rcl, -N(Me)S(O) 2 Rcl, -N(Et)S(O) 2 Rcl, -N(iPr)S(O) 2 Rcl and -N(nPr)S(O) 2 Rcl; Rc" corresponds to the group RC and 25 RC is as hereinbefore defined. -8- WO 2011/039344 PCT/EP2010/064628 In other preferred embodiments (D7)(D8)(D9) the present invention relates to compounds of the preferred embodiments (D4) and/or (D5) and/or (D6), wherein Rc" is selected from among C 1 4 alkyl, C 14 haloalkyl, C 3
-
5 cycloalkyl, C 14 alkoxymethyl,
(C
1
.
4 alkyl)NH-CH 2 - and (C 1
.
4 alkyl) 2
N-CH
2 -. 5 In other preferred embodiments (D1O)(D11)(D12) the present invention relates to compounds of the preferred embodiments (D4) and/or (D5) and/or (D6), wherein Rc is selected from among methyl and ethyl. In another preferred embodiment (D13) the present invention relates to compounds of general formulae (1a) and (1b), wherein 10 R 3 denotes -N(Me)S(O) 2 Me. In another preferred embodiment (El) the present invention relates to compounds of general formulae (1a) and (1b), wherein the group R 2 15 denotes
(R
7 )r R 6
R
6 and R 7 are defined as R 2 hereinbefore, r is equal to 1 or 2 and A is as hereinbefore defined. 20 In another preferred embodiment (E2) the present invention relates to compounds of general formulae (1a) and (1b), wherein A is a group selected from among phenyl and 5-10 membered heteroaryl and -9- WO 2011/039344 PCT/EP2010/064628
R
6 , R 7 and r are as hereinbefore defined. In another preferred embodiment (E3) the present invention relates to compounds of general formulae (1a) and (1b), wherein A is phenyl and 5 R 6 , R 7 and r are as hereinbefore defined. In another preferred embodiment (E4) the present invention relates to compounds of general formulae (1a) and (1b), wherein A is a phenyl; r has the value 1 or 2; 10 each R 7 is independently selected from among halogen, C 1
.
6 alkyl and C 1
.
6 alkoxy and
R
6 is as hereinbefore defined. In another preferred embodiment (E5) the present invention relates to compounds of general formulae (1a) and (1b), wherein A together with R 6 and the r substituents R 7 has the partial structure
R
7 a / R 7 c R4R
R
7 b R6 15 0) or
R
7 a and R 7 c each independently denote C 1
.
6 alkoxy;
R
7 b is selected from among halogen and C 1
.
6 alkyl and
R
6 is as hereinbefore defined. In another preferred embodiment (E6) the present invention relates to compounds of 20 general formulae (1a) and (1b), wherein A together with R 6 and the r substituents R 7 has the partial structure -10- WO 2011/039344 PCT/EP2010/064628
R
7 a
R
7 c R R 6
R
7 b R6 (i) or
R
7 a and R 7 c each independently denote methoxy;
R
7 b is selected from among fluorine, chlorine, methyl and ethyl and
R
6 is as hereinbefore defined. 5 In another preferred embodiment (E7) the present invention relates to compounds of general formulae (1a) and (1b), wherein A together with R 6 and the r substituents R 7 has the partial structure R7d R7 R 7f Ro R (iii) or (;v
R
7 d and R 7 * each independently of one another denote C 1
.
6 alkoxy; 10 R 7 f is selected from among halogen and C 1
.
6 alkyl and
R
6 is as hereinbefore defined. In another preferred embodiment (E8) the present invention relates to compounds of general formulae (1a) and (1b), wherein A together with R 6 and the r substituents R 7 has the partial structure -11- WO 2011/039344 PCT/EP2010/064628 R7d R7 R 7f RS R (iii) or (iv)
R
7 d and R 7 * each independently denote methoxy;
R
7 f is selected from among fluorine and methyl and
R
6 is as hereinbefore defined. 5 In other preferred embodiments (E9) the present invention relates to compounds of the preferred embodiments (El) to (E8), wherein
R
6 is selected from among hydrogen, Ra2, Rb 2 and Ra 2 substituted by one or more, identical or different Rb 2 and/or Rc 2 ; each Ra 2 is independently selected from among C 1
.
6 alkyl and 3-7 membered 10 heterocycloalkyl; each Rb 2 is a suitable substituent and is independently selected from among O=, -ORc 2 -NR c2 Rc2, -C(O)R c2, -C(O)OR c2, -C(O)NR c2 Rc2, -C(O)N(Rg2 )OR c2, -N(Rg2)C(O )R c2 -N(Rg2)C(O)ORc2 and -N(Rg2)C(O)NRc2Rc2 each Rc 2 independently denotes hydrogen or a group optionally substituted by one or 15 more, identical or different Rd 2 and/or Re 2 , selected from among C 1
.
6 alkyl, C 3
-
6 cycloalkyl and 3-7 membered heterocycloalkyl; each Rd 2 is a suitable substituent and is independently selected from among -ORe 2 -NRe 2 Re 2 , -C(O)N(Rg2)ORe2 and -C(O)NRe 2 Re 2 ; each Re 2 independently denotes hydrogen or a group optionally substituted by one or 20 more, identical or different R 2 and/or R2, selected from among C 1
.
6 alkyl, C 3
-
6 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl; each Rf 2 independently denotes -ORg2 and each Rg2 is independently selected from among hydrogen, C 1
.
6 alkyl and
C
4 .gcycloalkylalkyl. -12- WO 2011/039344 PCT/EP2010/064628 In other preferred embodiments (E1O) the present invention relates to compounds of the preferred embodiments (E9), wherein
R
6 denotes -C(O)NHRc 2 or -C(O)N(Me)Rc 2 and Rc 2 is as hereinbefore defined. 5 In other preferred embodiments (El) the present invention relates to compounds of the preferred embodiments (E9), wherein
R
6 denotes -NHC(O)Rc 2 or -N(Me)C(O)Rc 2 and Rc 2 is as hereinbefore defined. In other preferred embodiments (E12) the present invention relates to compounds of the 10 preferred embodiments (E9) to (El), wherein a heterocycloalkyl Ra 2 and/or Rc 2 is a heterocycloalkyl selected from among piperidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl and morpholinyl. In other preferred embodiments (E13) the present invention relates to compounds of the preferred embodiments (E9), wherein 15 R d enotes 0 'A N IN IN'Rc2 IN Rc2 R or and Rc 2 is as hereinbefore defined. In other preferred embodiments (E14) the present invention relates to compounds of the preferred embodiments (E9), wherein 20 R 6 denotes 0 All. N * IN R or and R* denotes C 1
.
6 alkyl. -13- WO 2011/039344 PCT/EP2010/064628 In other preferred embodiments (E15) the present invention relates to compounds of the preferred embodiments (E9), wherein
R
6 is selected from among NH NN H N N H N NNH NH NH -NaNH /Y 0
-N
0 J: ONH NH 0 NH 0 NH N N N N O O NH NH NH N N N~ N N0 NH NH HN O NH O 0N N N N ,NH O -14 -14- WO 2011/039344 PCT/EP2010/064628
O
O NH _(D NH - NH NH OH HO OH -N HN *NH j-I OH 0jN -TOH ONOO NOH H I I HO and HO In other preferred embodiments (E16) the present invention relates to compounds of the preferred embodiments (E9), wherein
R
6 is selected from among N N (-/"( N NN N N N -0 N NHO O (-N~ SNN N N N N 0. 0. N H N /NJ and HN 5 In other preferred embodiments (E17) the present invention relates to compounds of the preferred embodiments (E9), wherein
R
6 is selected from among -15- WO 2011/039344 PCT/EP2010/064628 N , , N H HN-' HN' N~ /N 0 0 N AHN~' HIt N NO and In other preferred embodiments (E18) the present invention relates to compounds of the preferred embodiments (E9), wherein
R
6 is selected from among O -O HN, OH O+A -N N 'N N \__/ NHNH N N and 5 In other preferred embodiments (E19) the present invention relates to compounds of the preferred embodiments (E9), wherein
R
6 is selected from among -16- WO 2011/039344 PCT/EP2010/064628 O ,0 NHN ('' H N N N/ N N , / and In other preferred embodiments the present invention relates to compounds of all the above-mentioned embodiments, wherein each Ra is independently selected from among C 1
.
6 alkyl, C 3
-
1 ocycloalkyl, 5 C 4
.
16 cycloalkylalkyl, C 6
.
1 oaryl, C 7
.
1 6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl; each Rb is a suitable group and is independently selected from among =0, -ORc,
C
1
-
3 haloalkyloxy, -OCF 3 , -NRcRc, -ONRcRc, -N(ORc)Rc, -N(Rg)NRcRc, halogen, -CF 3 , -CN, 10 -NO 2 , -S(O) 2 Rc, -S(O) 2 NRcRc, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -C(O)N(Rg)NRcRc, -C(O)N(Rg)ORc, -OC(O)Rc, -OC(O)NRcRc, -N(Rg)C(O)Rc, -N(OR9)C(O)Rc, -N(Rg)S(O)2Rc, -N(Rg)C(O)ORc and -N(Rg)C(O)NRcRc; each RC independently denotes hydrogen or a group optionally substituted by one or more, identical or different Rd and/or R*, selected from among C 1
.
6 alkyl, C 3
-
1 ocycloalkyl, 15 C 4
.
11 cycloalkylalkyl, C 6
.
1 oaryl, C 7
.
1 6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl; each Rd is a suitable group and is independently selected from among =0, -ORe,
C
1
-
3 haloalkyloxy, -OCF 3 , -NReRe, -ONReRe, -N(Rg)NReRe, halogen, -CF 3 , -CN, -NO 2 , 20 -S(O) 2 Re, -S(O) 2 NReRe, -C(O)Re, -C(O)ORe, -C(O)NReRe, -C(O)N(Rg)NReR, -C(O)N(Rg)ORe, -OC(O)Re, -OC(O)NReRe, -N(Rg)C(O)Re, -N(OR9)C(O)Re, -N(Rg)S(O)2Re, -N(Rg)C(O)ORe and -N(Rg)C(O)NReRe; each R* independently denotes hydrogen or a group optionally substituted by one or more, identical or different Rf and/or R9, selected from among C1.
6 alkyl, C 3
-
8 cycloalkyl, 25 C 4
.
11 cycloalkylalkyl, C 6
.
1 0 aryl, C 7
.
1 6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl; -17- WO 2011/039344 PCT/EP2010/064628 each Rf is a suitable group and is independently selected from among halogen, -OR9 and
-CF
3 and each R9 independently denotes hydrogen, C 1
.
6 alkyl, C 3
-
8 cycloalkyl, C 4 11 cycloalkylalkyl,
C
6
.
1 oaryl, C 7
.
1 6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 5 membered heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered heteroarylalkyl. All the above-mentioned preferred embodiments in terms of different molecular parts of the compounds according to the invention (1a) and (1b) may be combined with one another in any desired manner, thus producing preferred compounds (1a) and (1b) 10 according to the invention or generic partial amounts of preferred compounds according to the invention (1a) and (1b). Each individual embodiment or partial amount defined by this combination is expressly also included and is an object of the invention. Particularly preferred compounds are: 23 4-[4-((1 R,2R)-1 -methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin 2-ylamino]-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 24 2-fluoro-4-[4-((1 R,2R)-1 -methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl pyrimidin-2-ylamino]-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 25 2-fluoro-4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 27 4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 28 2-fluoro-4-[4-((1 R,2R)-2-methanesulphonylamino-cyclopentyloxy)-5-trifluoromethyl pyrimidin-2-ylamino]-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 29 4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-3-methoxy-N-((3S,4S)-3-methoxy-1 -methyl-piperidin-4-yl) benzamide 31 2-fluoro-4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-((3S,4S)-3-methoxy-1 -methyl piperidin-4-yl)-benzamide 74 2-chloro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) -18- WO 2011/039344 PCT/EP2010/064628 benzamide 75 2-fluoro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 77 4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-3-methoxy-N-(4-methyl-piperazin-1 -yl)-benzamide 79 3-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-4-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 84 2-chloro-4-{5-chloro-4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino) cyclopentyloxy]-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 85 4-{5-chloro-4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy] pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 88 4-{5-chloro-4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy] pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(4-methyl-piperazin-1 -yl)-benzamide 90 N-((1 R,2R)-2-{2-[4-(4-tert-butyl-piperazin-1 -yl)-2-methoxy-phenylamino]-5 trifluoromethyl-pyrimidin-4-yloxy}-indan-1 -yl)-N-methyl-methanesulphonamide 100 2-chloro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1 -yl) benzamide 101 2-fluoro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1 -yl) benzamide 102 2-chloro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 103 2-fluoro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 104 2-fluoro-4-[4-((1 R,2R)-2-methanesulphonylamino-cyclohexyloxy)-5-trifluoromethyl pyrimidin-2-ylamino]-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide -19- WO 2011/039344 PCT/EP2010/064628 The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives and prodrugs of compounds of general formula (1a) and (1 b). In another aspect the invention relates to compounds of general formula (1a) and (1b) or the pharmaceutically acceptable salts thereof - as medicaments. 5 In another aspect the invention relates to compounds of general formula (1a) and (1b) or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases. In another aspect the invention relates to compounds of general formula (1a) and (1b) or the pharmaceutically acceptable salts thereof - for use in the treatment and/or 10 prevention of cancer. In another aspect the invention relates to compounds of general formula (1a) and (1b) or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prevention of prostate cancer, ovarian cancer, pancreatic cancer and bronchial cancer. In another aspect the invention relates to a process for the treatment and/or prevention of 15 cancer comprising administering a therapeutically effective amount of a compound of general formula (1 a) or (1 b) - or one of the pharmaceutically acceptable salts thereof - to a person. In another aspect the invention relates to a pharmaceutical preparation containing as active substance one or more compounds of general formula (1a) and/or (1b) - or the 20 pharmaceutically acceptable salts thereof - optionally in combination with conventional excipients and/or carriers. In another aspect the invention relates to a pharmaceutical preparation comprising a compound of general formula (1 a) and/or (1 b) - or one of the pharmaceutically acceptable salts thereof - and at least one other cytostatic or cytotoxic active substance different from 25 formula (1a) and (ib). Definitions As used herein, the following definitions apply, unless stated otherwise: -20- WO 2011/039344 PCT/EP2010/064628 Alkyl is made up of the sub-groups saturated hydrocarbon chains and unsaturated hydrocarbon chains, while the latter may be further subdivided into hydrocarbon chains with a double bond (alkenyl) and hydrocarbon chains with a triple bond (alkynyl). 5 Alkenyl contains at least one double bond, alkynyl contains at least one triple bond. If a hydrocarbon chain were to carry both at least one double bond and also at least one triple bond, by definition it would belong to the alkynyl sub-group. All the sub-groups mentioned above may further be divided into straight-chain (unbranched) and branched. If an alkyl is substituted, the substitution may be mono- or polysubstitution in 10 each case, at all the hydrogen-carrying carbon atoms, independently of one another. Examples of representatives of individual sub-groups are listed below. Straight-chain (unbranched) or branched saturated hydrocarbon chains: methyl; ethyl; n-propyl; isopropyl (1-methylethyl); n-butyl; 1-methylpropyl; isobutyl (2-methylpropyl); sec.-butyl (1-methylpropyl); tert.-butyl (1,1-dimethylethyl); n-pentyl; 1 15 methylbutyl; 1-ethylpropyl; isopentyl (3-methylbutyl); neopentyl (2,2-dimethyl-propyl); n-hexyl; 2,3-dimethylbutyl; 2,2-dimethylbutyl; 3,3-dimethylbutyl; 2-methyl-pentyl; 3-methyl pentyl; n-heptyl; 2-methylhexyl; 3-methylhexyl; 2,2-dimethylpentyl; 2,3-dimethylpentyl; 2,4 dimethylpentyl; 3,3-dimethylpentyl; 2,2,3-trimethylbutyl; 3-ethylpentyl; n-octyl; n-nonyl; n decyl etc. 20 Straight-chain (unbranched) or branched alkenyl: vinyl (ethenyl); prop-1-enyl; allyl (prop-2-enyl); isopropenyl; but-1-enyl; but-2-enyl; but-3 enyl; 2-methyl-prop-2-enyl; 2-methyl-prop-1-enyl; 1-methyl-prop-2-enyl; 1-methyl-prop-1 enyl; 1-methylidenepropyl; pent-i-enyl; pent-2-enyl; pent-3-enyl; pent-4-enyl; 3-methyl but-3-enyl; 3-methyl-but-2-enyl; 3-methyl-but-i-enyl; hex-i-enyl; hex-2-enyl; hex-3-enyl; 25 hex-4-enyl; hex-5-enyl; 2,3-dimethyl-but-3-enyl; 2,3-dimethyl-but-2-enyl; 2-methylidene-3 methylbutyl; 2,3-dimethyl-but-1-enyl; hexa-1,3-dienyl; hexa-1,4-dienyl; penta-1,4-dienyl; penta-1,3-dienyl; buta-1,3-dienyl; 2,3-dimethylbuta-1,3-diene etc. Straight-chain (unbranched) or branched alkynyl: ethynyl; prop-1-ynyl; prop-2-ynyl; but-1-ynyl; but-2-ynyl; but-3-ynyl; 1-methyl-prop-2-ynyl 30 etc. -21- WO 2011/039344 PCT/EP2010/064628 By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, all the isomeric forms being included. By the terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl etc. 5 without any further definition are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a double bond, all the isomeric forms, i.e. (Z)I(E) isomers, being included where applicable. By the terms butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant unsaturated hydrocarbon groups 10 with the corresponding number of carbon atoms and two double bonds, all the isomeric forms, i.e. (Z)I(E) isomers, being included where applicable. By the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further definition are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a triple bond, all the isomeric forms being 15 included. By the term heteroalkyl are meant groups which can be derived from the alkyl as defined above in its broadest sense if, in the hydrocarbon chains, one or more of the groups -CH 3 are replaced independently of one another by the groups -OH, -SH or -NH 2 , one or more of the groups -CH 2 - are replaced independently of one another by the groups -0-, -S- or 20 -NH- , one or more of the groups H
-C
are replaced by the group
-N
one or more of the groups =CH- are replaced by the group =N-, one or more of the groups 25 =CH 2 are replaced by the group =NH or one or more of the groups =CH are replaced by the group =N, while overall there may only be a maximum of three heteroatoms in a heteroalkyl, there must be at least one carbon atom between two oxygen atoms and -22- WO 2011/039344 PCT/EP2010/064628 between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must be chemically stable. It is immediately apparent from the indirect definition/derivation from alkyl that heteroalkyl is made up of the sub-groups saturated hydrocarbon chains with 5 heteroatom(s), heteroalkenyl and heteroalkynyl, and one further subdivision may be carried out into straight-chain (unbranched) and branched. If a heteroalkyl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms, independently of one another. Heteroalkyl itself may be linked to the molecule as a substituent both via a 10 carbon atom and via a heteroatom. Typical examples are listed below: dimethylaminomethyl; dimethylaminoethyl (1- dimethylaminoethyl; 2-dimethyl-aminoethyl); dimethylaminopropyl (1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylamino propyl); diethylaminomethyl; diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl); 15 diethylaminopropyl (1-diethylaminopropyl, 2- diethylamino-propyl, 3-diethylaminopropyl); diisopropylaminoethyl (1-diisopropylaminoethyl, 2-di-isopropylaminoethyl); bis-2-methoxy ethylamino; [2-(dimethylamino-ethyl)-ethyl-amino]-methyl; 3-[2-(dimethylamino-ethyl) ethyl-amino]-propyl; hydroxymethyl; 2-hydroxy-ethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy; methoxymethyl; 2-methoxyethyl etc. 20 Halogen denotes fluorine, chlorine, bromine and/or iodine atoms. Haloalkyl is derived from alkyl as hereinbefore defined in its broadest sense, when one or more hydrogen atoms of the hydrocarbon chain are replaced independently of one another by halogen atoms, which may be identical or different. It is immediately apparent from the indirect definition/derivation from alkyl that haloalkyl is made up of the sub 25 groups saturated halohydrocarbon chains, haloalkenyl and haloalkynyl, and further subdivision may be made into straight-chain (unbranched) and branched. If a haloalkyl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon atoms, independently of one another. Typical examples include -CF 3 ; -CHF 2 ; -CH 2 F; -CF 2
CF
3 ; -CHFCF 3 ; -CH 2
CF
3 ; -CF 2
CH
3 ; 30 -CHFCH 3 ; -CF 2
CF
2
CF
3 ; -CF 2
CH
2
CH
3 ; -CF=CF 2 ; -CCI=CH 2 ; -CBr=CH 2 ; -CI=CH 2 ;
-C=C-CF
3 ; -CHFCH 2
CH
3 ; and -CHFCH 2
CF
3 . -23- WO 2011/039344 PCT/EP2010/064628 Cycloalkyl is made up of the sub-groups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings, while each sub-group may be further subdivided into saturated and unsaturated (cycloalkenyl). The term unsaturated 5 means that in the ring system in question there is at least one double bond, but no aromatic system is formed. In bicyclic hydrocarbon rings two rings are linked such that they have at least two carbon atoms in common. In spirohydrocarbon rings one carbon atom (spiroatom) is shared by two rings. If a cycloalkyl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon atoms, 10 independently of one another. Cycloalkyl itself may be linked to the molecule as substituent via any suitable position of the ring system. Typical examples of individual sub-groups are listed below. monocyclic saturated hydrocarbon rings: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl etc. 15 monocyclic unsaturated hydrocarbon rings: cycloprop-1-enyl; cycloprop-2-enyl; cyclobut-1-enyl; cyclobut-2-enyl; cyclopent-1-enyl; cyclopent-2-enyl; cyclopent-3-enyl; cyclohex-1-enyl; cyclohex-2-enyl; cyclohex-3-enyl; cyclohept-1-enyl; cyclohept-2-enyl; cyclohept-3-enyl; cyclohept-4-enyl; cyclobuta-1,3 dienyl; cyclopenta-1,4-dienyl; cyclopenta-1,3-dienyl; cyclopenta-2,4-dienyl; cyclohexa-1,3 20 dienyl; cyclohexa-1,5-dienyl; cyclohexa-2,4-dienyl; cyclohexa-1,4-dienyl; cyclohexa-2,5 dienyl etc. saturated and unsaturated bicyclic hydrocarbon rings: bicyclo[2.2.0]hexyl; bicyclo[3.2.0]heptyl; bicyclo[3.2.1]octyl; bicyclo[2.2.2]octyl; bicyclo[4.3.0]nonyl (octahydroindenyl); bicyclo[4.4.0]decyl (decahydronaphthalene); 25 bicyclo[2,2,1]heptyl (norbornyl); (bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl); bicyclo[2,2,1]hept-2-enyl (norbornenyl); bicyclo[4.1.0]heptyl (norcaranyl); bicyclo [3.1.1]heptyl (pinanyl) etc. saturated and unsaturated spirohydrocarbon rings: spiro[2.5]octyl, spiro[3.3]heptyl, spiro[4.5]dec-2-ene etc. -24- WO 2011/039344 PCT/EP2010/064628 Cycloalkylalkyl denotes the combination of the above-defined groups alkyl and cycloalkyl, in each case in their broadest sense. The alkyl group as substituent is directly linked to the molecule and is in turn substituted by a cycloalkyl group. The alkyl and cycloalkyl may be linked in both groups via any carbon atoms suitable for this purpose. 5 The respective sub-groups of alkyl and cycloalkyl are also included in the combination of the two groups. Aryl denotes mono-, bi- or tricyclic carbon rings with at least one aromatic ring. If an aryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon atoms, independently of one another. Aryl itself may be linked 10 to the molecule as substituent via any suitable position of the ring system. Typical examples include phenyl, naphthyl, indanyl (2,3-dihydroindenyl), 1,2,3,4 tetrahydronaphthyl and fluorenyl. Carbobicyclic ring systems comprise bicyclic carbon rings with at least one aromatic ring, such as for example bicyclooctatrienyl, indanyl, 1,2,3,4-tetrahydronaphthyl and 15 6,7,8,9-tetrahydrobenzocycloheptyl. Arvlalkyl denotes the combination of the groups alkyl and aryl as hereinbefore defined, in each case in their broadest sense. The alkyl group as substituent is directly linked to the molecule and is in turn substituted by an aryl group. The alkyl and aryl may be linked in both groups via any carbon atoms suitable for this purpose. The respective sub-groups 20 of alkyl and aryl are also included in the combination of the two groups. Typical examples include benzyl; 1-phenylethyl; 2-phenylethyl; phenylvinyl; phenylallyl etc. Heteroaryl denotes monocyclic aromatic rings, bi- or polycyclic ring systems with at least one aromatic ring, which, compared with corresponding aryl or cycloalkyl, contain 25 instead of one or more carbon atoms one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, while the resulting group must be chemically stable. If a heteroaryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another. Heteroaryl itself as 30 substituent may be linked to the molecule via any suitable position of the ring system, both carbon and nitrogen. -25- WO 2011/039344 PCT/EP2010/064628 Typical examples are listed below. monocyclic heteroaryls: furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; pyrazolyl; imidazolyl; triazolyl; tetrazolyl; oxadiazolyl; thiadiazolyl; pyridyl; pyrimidyl; pyridazinyl; pyrazinyl; 5 triazinyl; pyridyl-N-oxide; pyrrolyl-N-oxide; pyrimidinyl-N-oxide; pyridazinyl-N-oxide; pyrazinyl-N-oxide; imidazolyl-N-oxide; isoxazolyl-N-oxide; oxazolyl-N-oxide; thiazolyl-N oxide; oxadiazolyl-N-oxide; thiadiazolyl-N-oxide; triazolyl-N-oxide; tetrazolyl-N-oxide etc. bicyclic and polycyclic heteroarVIs: indolyl; isoindolyl; benzofuryl; benzothienyl; benzoxazolyl; benzothiazolyl; benzisoxazolyl; 10 benzisothiazolyl; benzimidazolyl; indazolyl; isoquinolinyl; quinolinyl; quinoxalinyl; cinnolinyl; phthalazinyl; quinazolinyl; benzotriazinyl; indolizinyl; oxazolopyridyl; imidazopyridyl; naphthyridinyl; indolinyl; isochromanyl; chromanyl; tetrahydroisoquinolinyl; isoindolinyl; isobenzotetrahydrofuryl; isobenzotetrahydrothienyl; isobenzothienyl; benzoxazolyl; pyridopyridyl; benzotetrahydrofuryl; benzotetrahydro-thienyl; purinyl; 15 benzodioxolyl; phenoxazinyl; phenothiazinyl; pteridinyl; benzothiazolyl; imidazopyridyl; imidazothiazolyl; dihydrobenzisoxazinyl; benzisoxazinyl; benzoxazinyl; dihydrobenz isothiazinyl; benzopyranyl; benzothiopyranyl; coumarinyl; isocoumarinyl; chromonyl; chromanonyl; tetrahydroquinolinyl; dihydroquinolinyl; dihydroquinolinonyl; dihydroiso quinolinonyl; dihydrocumarinyl; dihydroisocumarinyl; isoindolinonyl; benzodioxanyl; 20 benzoxazolinonyl; quinolinyl-N-oxide; indolyl-N-oxide; indolinyl-N-oxide; isoquinolyl-N oxide; quinazolinyl-N-oxide; quinoxalinyl-N-oxide; phthalazinyl-N-oxide; indolizinyl-N oxide; indazolyl-N-oxide; benzothiazolyl-N-oxide; benzimidazolyl-N-oxide; benzo thiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide etc. Heterobicyclic ring systems comprise for example dihydrobenzofuryl, dihydroiso 25 benzofuryl, dihydroindolyl dihydroisoindolyl, dihydrobenzothiophenyl, dihydroisobenzothio phenyl, dihydroindazolyl, 1,2-benzisoxazolyl, 1H-1,2-benzisoxazolyl, 1,2-benzothiazolyl, 2,3-tetrahydro-lH-isoquinolinyl, 3,4-tetrahydro-2H-isoquinolinyl, tetrahydroquinolinyl, chromanyl, isochromanyl, isochromenyl, thiochromanyl, thiochromenyl, dihydro-2H phthalazinyl, tetrahydrocinnolinyl, tetrahydroquinazolinyl, tetrahydrobenzodiazepinyl and 30 tetrahydrobenzoxazepinyl. -26- WO 2011/039344 PCT/EP2010/064628 Heteroarvialkyl denotes the combination of the alkyl and heteroaryl groups defined hereinbefore, in each case in their broadest sense. The alkyl group as substituent is directly linked to the molecule and is in turn substituted by a heteroaryl group. The linking of the alkyl and heteroaryl may be achieved on the alkyl side via any carbon atoms 5 suitable for this purpose and on the heteroaryl side by any carbon or nitrogen atoms suitable for this purpose. The respective sub-groups of alkyl and heteroaryl are also included in the combination of the two groups. By the term heterocycloalkyl are meant groups which are derived from the cycloalkyl as hereinbefore defined if in the hydrocarbon rings one or more of the groups -CH 2 - are 10 replaced independently of one another by the groups -0-, -S- or -NH- or one or more of the groups =CH- are replaced by the group =N-, while not more than five heteroatoms may be present in total, there must be at least one carbon atom between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must be chemically stable. Heteroatoms may simultaneously be 15 present in all the possible oxidation stages (sulphur - sulphoxide -SO-, sulphone-S0 2 -; nitrogen - N-oxide). It is immediately apparent from the indirect definition/derivation from cycloalkyl that heterocycloalkyl is made up of the sub-groups monocyclic hetero rings, bicyclic hetero-rings and spirohetero-rings, while each sub-group can also be further subdivided into saturated and unsaturated (heterocycloalkenyl). The term 20 unsaturated means that in the ring system in question there is at least one double bond, but no aromatic system is formed. In bicyclic hetero-rings two rings are linked such that they have at least two atoms in common. In spirohetero-rings one carbon atom (spiroatom) is shared by two rings. If a heterocycloalkyl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or 25 nitrogen atoms, independently of one another. Heterocycloalkyl itself as substituent may be linked to the molecule via any suitable position of the ring system. Typical examples of individual sub-groups are listed below. monocyclic heterorings (saturated and unsaturated): tetrahydrofuryl; pyrrolidinyl; pyrrolinyl; imidazolidinyl; thiazolidinyl; imidazolinyl; 30 pyrazolidinyl; pyrazolinyl; piperidinyl; piperazinyl; oxiranyl; aziridinyl; azetidinyl; 1,4 dioxanyl; azepanyl; diazepanyl; morpholinyl; thiomorpholinyl; homomorpholinyl; homopiperidinyl; homopiperazinyl; homothiomorpholinyl; thiomorpholinyl-S-oxide; -27- WO 2011/039344 PCT/EP2010/064628 thiomorpholinyl-S,S-dioxide; 1,3-dioxolanyl; tetrahydropyranyl; tetrahydrothiopyranyl; [1,4] oxazepanyl; tetrahydrothienyl; homothiomorpholinyl-S,S-dioxide; oxazolidinonyl; dihydropyrazolyl; dihydropyrrolyl; dihydropyrazinyl; dihydropyridyl; dihydro-pyrimidinyl; dihydrofuryl; dihydropyranyl; tetrahydrothienyl-S-oxide; tetrahydrothienyl-S,S-dioxide; 5 homothiomorpholinyl-S-o x i d e; 2 , 3-dihydroazet; 2H-pyrrolyl; 4H-pyranyl; 1,4 dihydropyridinyl etc. bicyclic heterorings (saturated and unsaturated): 8-azabicyclo[3.2.1]octyl; 8-azabicyclo[5.1.0]octyl; 2-oxa-5-azabicyclo[2.2.1]heptyl; 8-oxa 3-aza-bicyclo[3.2.1]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 2,5-diaza-bicyclo-[2.2.1]heptyl; 10 1-aza-bicyclo[2.2.2]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 3,9-diaza-bicyclo[4.2.1]nonyl; 2,6-diaza-bicyclo[3.2.2]nonyl; hexahydro-furo[3,2-b]furyl; etc. spiro-heterorincgs (saturated and unsaturated): 1,4-dioxa-spiro[4.5]decyl; 1-oxa-3,8-diaza-spiro[4.5]decyl; 2,6-diaza-spiro[3.3]heptyl; 2,7 diaza-spiro[4.4]nonyl; 2,6-diaza-spiro[3.4]octyl; 3,9-diaza-spiro[5.5]undecyl; 2,8-diaza 15 spiro[4.5]decyl etc. Heterocycloalkylalkyl denotes the combination of the alkyl and heterocycloalkyl groups defined hereinbefore, in each case in their broadest sense. The alkyl group as substituent is directly linked to the molecule and is in turn substituted by a heterocycloalkyl group. The linking of the alkyl and heterocycloalkyl may be achieved on the alkyl side 20 via any carbon atoms suitable for this purpose and on the heterocycloalkyl side by any carbon or nitrogen atoms suitable for this purpose. The respective sub-groups of alkyl and heterocycloalkyl are also included in the combination of the two groups. By the term suitable substituent is meant a substituent that on the one hand is fitting on account of its valency and on the other hand leads to a system with chemical stability. 25 By prodrug is meant an active substance in the form of its precursor metabolite. A distinction may be made between partly multi-part carrier-prodrug systems and biotransformation systems. The latter contain the active substance in a form that requires chemical or biological metabolisation. The skilled man will be familiar with prodrug 30 systems of this kind (Sloan, Kenneth B.; Wasdo, Scott C. The role of prodrugs in penetration enhancement. Percutaneous Penetration Enhancers (2nd Edition) (2006).51 -28- WO 2011/039344 PCT/EP2010/064628 64; Lloyd, Andrew W. Prodrugs. Smith and Williams' Introduction to the Principles of Drug Design and Action (4th Edition) (2006), 211-232; Neervannan, Seshadri. Strategies to impact solubility and dissolution rate during drug lead optimization: salt selection and prodrug design approaches. American Pharmaceutical Review (2004), 7(5), 108.110 5 113). A suitable prodrug contains for example a substance of the general formulae which is linked via an enzymatically cleavable linker (e.g. carbamate, phosphate, N-glycoside or a disulphide group to a dissolution-improving substance (e.g. tetraethyleneglycol, saccharides, amino acids). Carrier-prodrug systems contain the active substance as such, bound to a masking group which can be cleaved by the simplest possible 10 controllable mechanism. The function of masking groups according to the invention in the compounds according to the invention is to neutralise the charge for improving cell uptake. If the compounds according to the invention are used with a masking group, these may also additionally influence other pharmacological parameters, such as for example oral bioavailability, tissue distribution, pharmacokinetics and stability against non 15 specific phosphatases. The delayed release of the active substance may also involve a sustained-release effect. In addition, modified metabolisation may occur, thus resulting in a higher efficiency of the active substance or organic specificity. In the case of a prodrug formulation, the masking group or a linker that binds the masking group to the active substance is selected such that the prodrug is sufficiently hydrophilic to be dissolved in 20 the blood serum, has sufficient chemical and enzymatic stability to reach the activity site and is also sufficiently hydrophilic to ensure that it is suitable for diffusion-controlled membrane transport. Furthermore, it should allow chemically or enzymatically induced release of the active substance within a reasonable period and, it goes without saying, the auxiliary components released should be non-toxic. Within the scope of the invention, 25 however, the compound without a mask or linker, and a mask, may be regarded as a prodrug which first of all has to be prepared in the cell from the ingested compound by enzymatic and biochemical processes. List of abbreviations Bu butyl c concentration cHex cyclohexane d day(s) -29- WO 2011/039344 PCT/EP2010/064628 TLC thin layer chromatography DCM dichloromethane DIPEA N-ethyl-N,N-diisopropylamine (HOnig base) DMF NN-dimethylformamide DMSO dimethylsulphoxide EA ethyl acetate ESI electron spray ionization Et ethyl EtOH ethanol h hour(s) hex hexyl HPLC high performance liquid chromatography i iso IR infrared spectroscopy Me methyl MeOH methanol min minute(s) MPLC medium pressure liquid chromatography MS mass spectrometry NMP N-methylpyrrolidone NP normal phase Pd 2 dba 3 tris (dibenzylideneacetone)dipalladium(O) Ph phenyl rac racemic Rf (Rf) retention factor RP reversed phase RT ambient temperature temp. temperature tert. tertiary THF tetrahydrofuran tRet. retention time (HPLC) UV ultraviolet -30- WO 2011/039344 PCT/EP2010/064628 Features and advantages of the present invention will become apparent from the following detailed Examples which illustrate the fundamentals of the invention by way of example, without restricting its scope: 5 Preparation of the compounds according to the invention General All the reactions are carried out - unless stated otherwise - in commercially obtainable apparatus using methods conventionally used in chemical laboratories. 10 Air- and/or moisture-sensitive starting materials are stored under protective gas and corresponding reactions and manipulations using them are carried out under protective gas (nitrogen or argon). Microwave reactions are carried out in an Initiator made by Biotage or an Explorer made 15 by CEM in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring. Chromatography For the preparative medium pressure chromatography (MPLC, normal phase) silica gel is used which is made by Millipore (named: Granula Silica Si-60A 35-70 pm) or C-18 RP 20 silica gel (RP-phase) made by Macherey Nagel (named: Polygoprep 100-50 C18). The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck. 25 The preparative high pressure chromatography (HPLC) is carried out using columns made by Waters (named: XTerra Prep. MS C18,5 pM, 30 x 100mm orXTerra Prep. MS C18, 5 pm, 50 x 100 mm OBD or Symmetrie C18, 5 pm, 19 x 100 mm or Sunfire C18 OBD, 19 x 100 mm, 5 pm or Sunfire Prep C 10 pm OBD 50 x 150 mm or X-Bridge Prep C18 5 pm OBD 19 x 50 mm), Agilent (named: Zorbax SB-C8 5 pm PrepHT 21.2 x 50 mm) and 30 Phenomenex (named: Gemini C18 5 pm AXIA 21.2 x 50 mm or Gemini C18 10 pm 50 x 150 mm), the analytical HPLC (reaction control) is carried out with columns made by Agilent (named: Zorbax SB-C8, 5 pm, 21.2 x 50 mm or Zorbax SB-C8 3.5 pm 2.1 x 50 mm) and Phenomenex (named: Gemini C18 3 pm 2 x 30 mm). -31- WO 2011/039344 PCT/EP2010/064628 HPLC mass spectroscopy/UV spectrometry The retention times/MS-ESI for characterising the examples are obtained using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made 5 by Agilent. Compounds that elute with the injection peak are given the retention time tRet. = 0.00. Method A Column: Waters, Xterra MS C18, 2.5 pm, 2.1 x 30 mm, Part.No. 186000592 10 Eluant: A: H 2 0 with 0.1% HCOOH; B: acetonitrile (HPLC grade) Detection: MS: Positive and negative mode Mass range: 120 - 900 m/z Fragmentor: 120 Gain EMV: 1; Threshold: 150; Stepsize: 0.25; UV: 254 nm ; Bandwidth: 1 15 Injection: Inj. Vol. 5 pL Separation: Flow 1.10 mL/min Column temp.: 40 0 C Gradient: 0.00 min: 5 % solvent B 0.00 - 2.50 min: 5 % -> 95 % solvent B 20 2.50 - 2.80 min: 95 % solvent B 2.81 - 3.10 min: 95 % -> 5 % solvent B Method B Column: Waters, Xterra MS C18, 2.5 pm, 2.1 x 50 mm, Part.No. 186000594 Eluant: A: H 2 0 with 0.1 % HCOOH; B: acetonitrile with 0.1 % HCOOH 25 Detection: MS: Positive and negative mode Mass range: 100 - 1200 m/z Fragmentor: 70 Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 254 nm as well as 230 nm Injection: Standard 1 pL 30 Flow: 0.6 mL/min Column temp.: 35 0 C Gradient: 0.00 min: 5 % solvent B 0.00 - 2.50 min: 5 % -> 95 % solvent B -32- WO 2011/039344 PCT/EP2010/064628 2.50 - 4.00 min: 95 % solvent B 4.00 - 4.50 min: 95 % -> 5 % solvent B 4.50 - 6.00 min: 95 % solvent A Method C 5 Column: Waters, X-Bridge C18, 3.5 pm, 2.1 x 50 mm, Eluant: A: H 2 0 with 10mM NH 3 ; B: acetonitrile with 10 nM NH 3 Detection: MS: Positive and negative mode Mass range: 100 - 800 m/z Fragmentor: 70 10 Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1 pL Flow: 0.8 mL/min Column temp.: 25 OC Gradient: 0.00 min: 2 % solvent B 15 0.00 - 4.00 min: 2 % -> 98 % solvent B 4.00 - 6.00 min: 98 % solvent B Method D Column: Waters, X-Bridge C18, 3.5 pm, 2.1 x 50 mm, Eluant: A: H 2 0 with 0.1 % HCOOH; B: acetonitrile with 0.1 % HCOOH 20 Detection: MS: Positive and negative mode Mass range: 100 - 800 m/z Fragmentor: 70 Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1 pL 25 Flow: 0.8 mL/min Column temp.: 35 OC Gradient: 0.00 min: 2 % solvent B 0.00 - 4.00 min: 2 % -> 98 % solvent B 4.00 - 6.00 min: 98 % solvent B 30 Method E Column: Phenomenex Gemini C18, 3.0 pm, 2.0 x 50 mm, Eluant: A: H 2 0 with 10 mM NH 3 ; B: acetonitrile with 10 nM NH 3 Detection: MS: Positive and negative mode Mass range: 100 - 800 m/z -33- WO 2011/039344 PCT/EP2010/064628 Fragmentor: 70 Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1 pL Flow: 1.0 mL/min 5 Column temp.: 35 OC Gradient: 0.00 min: 2 % solvent B 0.00 - 3.50 min: 2 % -> 98 % solvent B 3.50 - 6.00 min: 98 % solvent B Method F 10 Column: Phenomenex Gemini C18, 3.0 pm, 2.0 x 50 mm, Eluant: A: H 2 0 with 0.1 % HCOOH; B: acetonitrile with 0.1 % HCOOH Detection: MS: Positive and negative mode Mass range: 100 - 800 m/z Fragmentor: 70 15 Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1 pL Flow: 1.0 mL/min Column temp.: 35 OC Gradient: 0.00 min: 2 % solvent B 20 0.00 - 3.50 min: 2 % -> 98 % solvent B 3.50 - 6.00 min: 95 % solvent B The compounds according to the invention are prepared by the methods of synthesis described below, in which the substituents of the general formulae have the meanings 25 specified hereinbefore. These methods are intended to illustrate the invention without restricting it to their content or limiting the scope of the compounds claimed to these Examples. Where the preparation of the starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according 30 to the published methods of synthesis. -34- WO 2011/039344 PCT/EP2010/064628 Reaction scheme A R1 R1 R4 I R zO R O'Rz NyN + HO N'Y N + H 2 N ' N N Cl Cl R NH A-1 A-2 I R 1 R 1 R4 Cl R Cl R0z ORz N Y N + H 2 N ' NN + HO' ' N N Cl R NH R NH A-1 A-3 I Example compounds of type I are prepared from 2,4-dichloropyrimidines A-1 substituted by R 1 , by nucleophilic aromatic substitution using an alcohol Rz-OH and an amine Rz-NH 2 . 5 The order of substitution depends to a great extent on the nucleophiles used, the reaction conditions (acidic or basic reaction conditions and the addition of Lewis acids) and the substituent R 1 . Ry and Rz are in each case suitable groups for obtaining Example compounds according to the invention. 10 The nucleophilic aromatic substitutions at A-1, A-2 and A-3 are carried out according to methods known from the literature in common solvents, such as e.g. THF, DCM, NMP, EtOH, MeOH, DMSO or DMF using a base, such as for example DIPEA, Cs2CO3 or NaH or an acid such as for example HCI. The amines R -NH 2 used, and the alcohols Rz-OH are commercially obtainable or are synthesised according to methods known from the 15 literature. The 2-amino-4-oxo-pyrimidines of type I which may be obtained directly by these methods may then be further modified in Ry and Rz in a manner known from or analogous to the literature to form further 2-amino-4-oxo-pyrimidines of type 1. Thus, for example, the groups Ry and Rz of directly obtainable 2-amino-4-oxo-pyrimidines of type 1, which consist of a carboxylic acid-, sulphonic acid-, halogen- or amino-substituted aryl, 20 heteroaryl, cycloalkyl or heterocycloalkyl, may be modified by reactions of substitution (at the heteroaryl itself), alkylation, acylation, amination or addition. -35- WO 2011/039344 PCT/EP2010/064628 Preparation of the starting compounds If their preparation is not described, the starting materials are commercially obtainable, known from the literature or easily obtainable by the skilled man using general methods, for example 5 4-amino-2-chloro-5-methoxy-benzoic acid, 4-amino-2-fluoro-5-methoxy-benzoic acid (WO 2008/003958); 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-yl-amino)-3-methoxy-benzoic acid, 4-(4-chloro-5 trifluoromethyl-pyrimidin-2-yl-amino)-2-chloro-5-methoxy-benzoic acid and 4-(4-chloro-5 trifluoromethyl-pyrimidin-2-yl-amino)-2-fluoro-5-methoxy-benzoic acid (analogously to 10 WO 2007/003596); tert-butyl 4-benzylamino-3-fluoro-piperidine-1-carboxylate (J. Med. Chem. 1999, 42(12), 2087-2104); benzyl (3S,4S)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate and benzyl (3R,4R)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1 -carboxylate 15 (WO 2004/058144). 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1 -methyl-piperidin 4-yi)-benzamide F F F F F C1 F I N C N N 1) SOC1 2 , Toluol N O + - N N N 2) DIPEA, THF N N 0 7&0 0 Y& N rN 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoic acid (2.0 g) is suspended in 20 70 mL toluene, mixed with thionyl chloride (0.84 mL) and heated to 120 'C for 2 h with stirring. The reaction mixture is left to cool to RT and the solvent is eliminated using the rotary evaporator. The residue is suspended in 50 mL THF, cooled to 0 'C and a solution of 4-amino-1-methylpiperidine (0.66 g) and DIPEA (1.97 mL), dissolved in 20 mL THF, is added dropwise. The reaction mixture is slowly brought up to RT and stirred for a further -36- WO 2011/039344 PCT/EP2010/064628 12 h at RT. The reaction mixture is cooled to 0 'C, the product is filtered off and used without any further purification. N-((1 R,2R)-2-hydroxy-indan-1 -yI)-N-methyl-methanesulphonamide a) (1 R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1 -Vlamine DCM, NEt 3 N
-
+ -S cl 5 (1R,2R)-1-amino-2-indanol (2.00 g) is suspended in 20 mL DCM and combined with triethylamine (3.61 mL) as well as DMAP (0.32 g). Then tert-butyldimethylchlorosilane (4.04 g in 2 mL CH 2
CI
2 ) is added. The reaction mixture is stirred for 16 h at RT and, once the reaction is complete, it is mixed with water, extracted with CH 2 Cl 2 and the organic 10 phase is freed from the solvent using the rotary evaporator. The residue is taken up in MeOH and isolute is added. After elimination of the solvent once again the mixture is purified by normal phase chromatography (CH 2
CI
2 /EA). The product-containing fractions are combined and freed from the solvent using the rotary evaporator. b) N-[(1 R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1 -vll-methanesulphonamide N
CH
3
SO
2 CI 'O O
CH
2
CI
2 ',N \/- 0 15 (1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-ylamine (1.60 g) is dissolved in 16 mL DCM and combined with triethylamine (2.54 mL). Then methanesulphonyl chloride (0.61 mL in 5mL DCM) is added dropwise. The reaction mixture is stirred for 2 h and after elimination of the solvent it is purified by normal phase chromatography (cHex/EA). The 20 product-containing fractions are combined and freed from the solvent using the rotary evaporator. -37- WO 2011/039344 PCT/EP2010/064628 c) N-[(1 R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1 -yll-N-methyl-methanesulphon amide .. N, 0 Mel 4O K 2
CO
3
--
N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-methanesulphonamide (0.50 g) is 5 dissolved in 2 mL DMF and mixed with Cs2CO3 (0.96 g, 2.93 mmol) and Mel (0.10 mL). The reaction mixture is stirred for 2 h and, once the reaction has ended, combined with DCM and NaOH (1 N). The organic phase is dried on MgSO 4 and freed from the solvent using the rotary evaporator. After dissolving in acetonitrile water is added. The precipitate formed is filtered off, washed with water and taken up in DCM. After drying on MgSO 4 the 10 solvent is eliminated using the rotary evaporator. d) N-((1 R,2R)-2-hydroxy-indan-1 -yl)-N-methyl-methanesulphonamide 4S i. Bu 4 NF 0 Si, || THF || 0 - 0 N-[(1 R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1 -yl]-N-methyl-methanesulphonamide (0.53 g) is dissolved in 5 mL THF, combined with Bu 4 NF (5mL of a 1 N solution in THF) 15 and stirred for 2 h at RT. After the reaction is complete the reaction mixture is freed from the solvent. After the addition of CH 2 Cl 2 it is extracted with HCI (aqu., 1 N). The organic phase is dried on MgSO 4 . After elimination of the solvent the mixture is purified by normal phase chromatography (CH 2
CI
2 , MeOH). The product-containing fractions are combined and freed from the solvent using the rotary evaporator. 20 -38- WO 2011/039344 PCT/EP2010/064628 N-((1 R.2R)-2-hydroxy-indan-1 -yi)-acetamide 0 0 N O O DCM N o (1R,2S)-1-amino-2-indanol (2.0 g) is suspended in 100 mL CH 2
CI
2 and at RT combined 5 with acetic anhydride (1.27 mL). The reaction mixture is stirred for 1 h at RT. After the reaction has ended the solvent is eliminated using the rotary evaporator and the crude product (HPLC-MS: tRet. = 0.81 min; MS (M+H)* = 192) is used in subsequent reactions without further purification. Preparation of the End Compounds 10 Example 26: 4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-tri fluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide a) 4-[4-((1 R,2R)-2-amino-cyclopentyloxy)-5-trifluoromethyl-pyrimidin-2-Vlaminol-3 methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide F F F F F o NyN +N NaH O NYN o N 0 N N N N 15 (R,R)-2-aminocyclopentanol x HCI (155 mg) is added to a suspension of NaH (135.2 mg) in dioxane (0.75 mL) and stirred for 30 min at RT. Then 4-(4-chloro-5-trifluoromethyl pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (250 mg) is added. After 18 h, H 2 0 (50 mL) is added. The precipitate formed is filtered off, washed with H 2 0, dissolved in CH 2
CI
2 and extracted with aqueous KHSO 4 solution (10 %). The aqueous 20 phase is made basic again with K 2
CO
3 and extracted with CH 2
CI
2 . The organic phase is dried on magnesium sulphate, filtered to remove the desiccant and the solvent is eliminated in vacuo. -39- WO 2011/039344 PCT/EP2010/064628 b) 4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxyl-5-trifluoromethyl pyrimidin-2-ylamino}-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide F F F F F F N N CH 3
SO
2 CI N N 0 0 07 N N N N N ,N r N 4-[4-((1 R.2R)-2-amino-cyclopentyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy 5 N-(1-methyl-piperidin-4-yl)-benzamide (0.26 g) is dissolved in 4 mL CH 2 Cl 2 and mixed with DIPEA (0.11 mL). Then methanesulphonyl chloride (0.05 mL) is added. The reaction mixture is stirred for 18 h and purified by preparative HPLC without any further pre purification. The product-containing fractions are combined and freed from the solvent by freeze-drying. 10 Example 27: 4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoro methyl-pyrimidin-2-ylamino}-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide F F F F F \ ,P F 0 N-S CI Cl N' N O N N O , 0 Cs2CO ON + 'S N N 0 0 N N N Nr NN 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide (50 mg) and N-((1R,2R)-2-amino-indan-1-yl)-methanesulphonamide N 15 ((1 R,2R)-2-hydroxy-indan-1 -yl)-N-methyl-methanesulphonamide (54.4 mg) are suspended in dioxane (0.6 mL), mixed with Cs 2
CO
3 (184 mg) as well as some MgSO 4 and stirred overnight at 85 'C. The reaction mixture is left to cool to RT, MeOH and isolute are added -40- WO 2011/039344 PCT/EP2010/064628 thereto and the solvent is eliminated using the rotary evaporator. Purification is carried out by preparative HPLC. Example 68: 4-[4-((1R,2R)-1-acetylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2 ylamino]-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide F F F F F 0 SCI N N N O DIPEA, EtOH O N N SN 0 N N N-((1R,2R)-2-hydroxy-indan-1-yl)-acetamide (43 mg) and 4-(4-chloro-5-trifluoromethyl pyrimidin-2-ylamino)-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide (50 mg) are suspended in 0.70 mL dioxane, mixed with Cs2CO3 (184 mg) and some MgSO 4 and stirred overnight at 85 OC. The reaction mixture is allowed to cool to RT and the solvent is 10 eliminated using the rotary evaporator. The residue is taken up in MeOH and purified by preparative HPLC. The product-containing fractions are freeze-dried. Analogously to the syntheses in Examples 26, 27 and 68 as described above, the following Examples in the Table and comparable additional examples may be obtained from the corresponding precursors, which are either commercially obtainable or are 15 obtained by methods known from the literature. -41- WO 2011/039344 PCT/EP2010/064628 Table 1: Examples 1 - 111 No. Structure MS (M+H)* tRet [mi] F F 0 N-N 1_F 600 2.05 F FF N N 0 0 0 F F 0 XF 0 N-S ' 0 0r N \ r 2 F N 641 2.12 0 N N N F F 0/ o 6O N f F F N 3 640 2.38 0 N 10 F N -42- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F 09 0 0 YN F N 5 696 2.03 0 0 N N F F0 F F N-S 6 F N 584 2.05 0 0;)0 N 0 0, N-f~ 7 0> 0790 2.26 N0 N F F 0 F N-S. N I>yN F N 0 8 1655 2.16 N N, F4 0 F N 3 0 \1 9F N624 2.24 0 -43- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F < F N S N >NO 10 F N 668 2.03 O ON F F / F N-S. o, 0 N >NO F N 668 2.02 O F NyN N 0a F N-S N wN N 00 N F F N F No I F0 d- 1 N <N 13 660 1.92 0 N N F F 0 F 0 N-S ' 14 N 623 1.85 0 W N -44- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F 0 ,71 N S 0 0 N 15 622 2.07 0 N F F 0 F N S 0 0 N 16 678 1.77 0F N N F, / 0 FF N-S o o N N " 17 566 1.76 N N F F 9 F N-S, 18 0. 772 2.00 F F '0 F N-S. y0 0 N -N 19 N 650 1.70 0a N -45- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F 0 F N 0 0 ,, -N 20 0 637 2.11 N N, F [0 F N--S N N 21 N 606 2.12 0 0 oN F F O F N-S O 0 N -F 22 N 650 1.97 0 00 NN F F O F NS y0 01 NyN 23 N 635 1.96 0 gN N F F p0 NNN 24 0F N 653 2.01 00 N Na -46- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F O F N-S 0 0 25 F N 667 2.10 O 7N N N F F N 0 O N 26 587 1.80 N 0 N F F 0O F
N-S
3 N 27 649 1.99 0 7N N N F F N> N N 0 O N, 28 F 605 1.89 N- 0 N F F O F N S 0 0 NN 29 N 679 1.94 N N-7 -47- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F N N 0 30 ,rN 621 1.87 N 0 N F F 0 F N S 0 0 N N F N 31 697 2.08 0N N 0 F" F < F N 32 N 649 1.98 0 CN N CI N ,N 0 33 532 1.88 CI o N 0 N' N 0 0 34 C1678 1.92 0 N CN N -48- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] CI 9 IN N-S 0 UO 35 660 1.87 CI N N N
C
N CI 7 N O O Nt N 0 36 626 1.77 Cl <0 o N O 0 N O 0 37 580 2.02 Cl O N 38 0- 582 1.50 'Cl 0 NI 11t 39 U622 2.20 ClI 0 N -49- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Nc N N N 0 40 0 623 1.94 O N C CI N N 0 N ) 41 637 2.02 o N N O 42 c 626 1.77 0 N sO0 0 0 N N 43 N F 566 1.69 F N N<F >,N >0O 44 F 619 2.05 0 N -50- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F N 0 N 0 45 F o 639 2.05 F N NF N
-
OI 46 F Z 631 2,04 N NF N 0 S 0 47 el c) 655 1.92 0 N F N- N F N 48 C'o 647 1.96 O N F F NN 0 47 \i 655 19 SN 49 66. N 49 0 i 647 1.96 0 0 y0TI N -O 0 -51- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F 0 F N S 500 0 N N 50 N N 626 1.82 0 N 0 N N 51 N F 0 610 1.83 N N o N CI 52 N, F 644 1.91 N 0 0 N N 53 N F 0 607 2.06 "No 0 0 N N 54 NI- F 0 1564 2.02 -52- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] 0 N N 55 N N C N 55 h I 634 1.97 0 F 0 f ON 0 0 O N N 56 N F 608 1.80 Oj 0 00 CI 57 N F 662 1.98 NN N O N 0 N 58 N N 756 2.22 N O F 0 / 0 N N N 59 F634 1.88 50 -53- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] 0 N N 60 0 F 60 N IF 621 2.18 N0 F N> F N N0 N 61 F606 1.77 N 0 NO unirai 0 N- N 0 62 649 1.97 O N N Chiral N N ~N 0 63 650 1.85 N CI F F F N-S N I N 64 F N 644 1.88 N 0 -54- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] F F 0 0 F N 65 644 1.87 N 0 0 0 N 66 NF590 2.31 N NIF 0 Chiral N N 67 550 2.06 N Chiral N F N N O 68 N 599 1.83 Chiral F F F F N S \ 69 N 649 2.00 0- 0 NN N -55- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral F F FN~ 0 0 70 N 649 1.99 0 CN N Chiral 71 F 635 1.85 Nj~ SO Chiral O F N F F 72 N 599 1.84 0 Chiral F N> F F ON 0 74 588 1.66 o N N Chiral F N> FF N N 0 .N,< N4CI r 649 1.93 -56- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral F N O- NO 75 633 1.98 O N Chiral F A F F 0N N 76 [ 615 1.90 O N Chiral F N> F F N N o .N N0 77 [ < 616 1.76 O N N Chiral F F N F 78 0 ... N D 595 1.87 N 0 N Chiral N 79 F F 649 1.95 0 F 0 -57- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral N N 0 F 80 N F F 650 1.82 0 Chiral F N F N N 0 81 0N 01"' _ 623 1.96 N Chiral F N F N' N 82 0 \ 0 637 2.01 N8N N Chiral F 83 N'N 0 472 .82 0 Ch iral N N O 0S O 84 CI o 601 1.84 0 N N -58- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [min Chiral ON S O 85 OJNF O 585 1.89 ON Chiral \F N' N' O 86 N4 1.8 CI Chiral FF N N F N O N N O Y NJ S OD ON Chiral N N C ON O 889 IF 056 1.72 N N -59 WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral -P F F N 90 649 2.35 N 0 N Chiral F F 0 F N 91 NrN 649 2.04 N 0 Chiral F F 0 0 S 0 AN 92 N 649 2.12 N N Chiral 0 F F N s F NS 93 635 1.85 N CI N Chiral F 0 O FN 94 N 566 1.94 N -60- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral F F N I N N 0 95 [609 1.90 N O Chiral F F N I N N 0 96 70627 2.02 N 0 N Chiral F F 99I F .. N15920 97 S- N -- N 474 1.82 N' ~-61 0 Ch iral F W< F 98 F606 1.73 N O Ch iral F ,F F N 0 >0 INO 99 [ 34 579 2.02 F N 0 N-61 WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral F N F O Nf 100 cl 636 1.85 N N Chiral F
N
7 F [F O N N O 101 F 620 1.81 0 N N Chiral F
N
7 F N N 0 0 N O 102 c si 635 1.89 0 N O Chiral F
N
7 F O N O 103 7 F 619 2.04 0 N N Chiral 0 F F NS F N 104 N601 1.82 N 0 N N
N
-62- WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral 0 F F s F N 0 0 105 619 1.90 N F N Chiral F F So -0 106 NN 593 1.92 N 0 Chiral F F N> N N0 0 N O 107 F F&F 659 1.48 0 N N Chiral F S 10 Chiral F F F 0 N 109 SNN 623 1.96 N CI 0 N
N
7 -F -6F WO 2011/039344 PCT/EP2010/064628 No. Structure MS (M+H)* tRet [mi] Chiral F
N
7 F N N O 110 [ 607 2.00 0 N N Chiral F N F N N O 111 N 589 1.90 O N N The following Examples describe the biological activity of the compounds according to the invention without restricting the invention to these Examples. PTK2 Enzyme tests 5 Assay 1 This test uses active PTK2 enzyme (Invitrogen Code PV3832) and poly-Glu-Tyr (4:1, Sigma P-0275) as the kinase substrate. The kinase activity is detected through the phosphorylation of the substrate in a DELFIATM assay. The phosphorylated substrate is detected with the europium-labelled phosphotyrosine antibody PT60 (Perkin Elmer, No.: 10 AD00400). In order to determine concentration-activity curves with PTK2-inhibitors the compounds are serially diluted in 10 % DMSO/H 2 0 and 10 pL of each dilution are placed in each well of a 96-well microtitre plate (clear plate with a U-shaped base, Greiner No. 650101) (the inhibitors are tested in duplicates) and mixed with 10 pL/well of PTK2 kinase 15 (0.01 pg/well). PTK2 kinase has been correspondingly diluted beforehand with kinase dilution buffer (20 mM TRIS/HCI pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10 % glycerol with the addition of freshly prepared BSA (fraction V, 1 mg/mL) and DTT (1 mM)). The test compound and the PTK2 kinase are pre-incubated -64- WO 2011/039344 PCT/EP2010/064628 for 1 h at RT and shaken at 500 revolutions per min. The reaction is started by the addition of 10 pL/well poly (Glu,Tyr) substrate (25 pg/well poly (Glu, Tyr), 0.05 pg/well biotinylated poly (Glu,Tyr) dissolved in 250 mM TRIS/HCI pH 7.5, 9 mM DTT)- the final concentration of DMSO is 2 %. Then 20 pL of ATP Mix (30 mM TRIS/HCI pH 7.5, 0.02 % 5 Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA, 1x phosphatase inhibitor cocktail 1 (Sigma, No.: P2850), 50 pM ATP (Sigma, No.: A3377; 15 mM stock solution)) are added. After 1 h of kinase reaction (the plates are shaken at 500 rpm), the reaction is stopped by the addition of 12 pL/well 100 mM EDTA, pH 8.0 and shaken for a further 5 min at RT (500 rpm). 55 pL of the reaction mixture are transferred 10 into a streptavidin plate (Strepta Well High Bind (transparent, 96-well) made by Roche, No.: 11989685001) and incubated for 1 h at RT (shaking at 500 rpm). Then the microtitre plate is washed three times with 200 pL/well D-PBS (Invitrogen, No. 14190). 100 pL of a solution containing DELFIA Eu-N1 Anti-Phosphotyrosine PT60 antibody (Perkin Elmer, No.: AD0040, diluted 1:2000 in DELFIA test buffer (Perkin Elmer, No.: 1244-111)) is then 15 added and the mixture is incubated for 1 h at RT (shaking at 500 rpm). Then the plate is washed three times with 200 pL/well DELFIA washing buffer (Perkin Elmer, No.: 1244 114), 200 pL/well strengthening solution (Perkin Elmer, No.: 1244-105) are added and the mixture is incubated for 10 min at RT (shaking at 300 rpm). The time-delayed europium fluorescence is then measured in a microtitre plate reader 20 (VICTOR 3 , Perkin Elmer). The positive controls used are wells that contain the solvent controls (2 % DMSO in test buffer) and exhibit uninhibited kinase activity. Wells that contain test buffer instead of enzyme are used as a control of the background kinase activity. The IC50 values are determined from analyses of the concentration activity by iterative 25 calculation with the aid of a sigmoid curve analysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a variable Hill coefficient. Assay 2 This test uses active PTK2 enzyme (Invitrogen Code PV3832) and poly-Glu-Tyr (4:1, Sigma P-0275) as the kinase substrate. The kinase activity is detected by means of the 30 phosphorylation of the substrate in a DELFIATM assay. The phosphorylated substrate is detected with the europium-labelled phosphotyrosine antibody PT66 (Perkin Elmer, No.: AD0040). -65- WO 2011/039344 PCT/EP2010/064628 In order to determine concentration-activity curves with PTK2-inhibitors the compounds are serially diluted first of all in 100 % DMSO and then in kinase dilution buffer (20 mM TRIS/HCI pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10 % glycerol with the addition of freshly prepared BSA (fraction V, 1 mg/mL) and DTT (1 mM)) 5 and 10 pL of each dilution are dispensed per well in a 96-well microtitre plate (clear U shaped base plate, Greiner No. 650101) (the inhibitors are tested in duplicates) and mixed with 10 pL/well of PTK2 kinase (0.01 pg/well). PTK2 kinase is diluted accordingly beforehand with kinase dilution buffer. The diluted PTK2 inhibitor and the PTK2 kinase are pre-incubated for 1 h at RT and shaken at 500 revolutions per min. Then 10 pL/well 10 poly-Glu-Tyr substrate (25 pg/well poly-Glu-Tyr, 0.05 pg/well biotinylated poly-Glu-Tyr dissolved in 250 mM TRIS/HCI pH 7.5, 9 mM DTT) are added. The reaction is started by the addition of 20 pL of ATP Mix (30 mM TRIS/HCI pH 7.5, 0.02 % Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA, 1x phosphatase inhibitor cocktail 1 (Sigma, No.: P2850), 50 pM ATP (Sigma, No.: A3377; 15 mM stock solution)) 15 the final concentration of DMSO is 0.5 %. After 1 h kinase reaction (the plates are shaken at 500 rpm), the reaction is stopped by the addition of 12 pL/well of 100 mM EDTA, pH 8, and shaken for a further 5 min at RT (500 U/min). 55 pL of the reaction mixture are transferred into a streptavidin plate (Strepta Well High Bind (transparent, 96-well) made by Roche, No.: 11989685001) and incubated for 1 h at RT (shaking at 500 rpm). Then the 20 microtitre plate is washed five times with 200 pL/well D-PBS (Invitrogen, No. 14190). 100 pL of a solution containing DELFIA Eu-N1 Anti-Phosphotyrosine PT66 antibody (Perkin Elmer, No.: AD0040, diluted 1:9000 in DELFIA test buffer (Perkin Elmer, No.: 1244-111)) is then added and it is incubated for 1 h at RT (shaking at 500 rpm). Then the plate is washed five times with 200 pL/well DELFIA washing buffer (Perkin Elmer, No.: 25 1244-114), 200 pL/well strengthening solution (Perkin Elmer, No.: 1244-105) is added and the whole is incubated for 10 min at RT (shaking at 300 rpm). The time-delayed europium fluorescence is then measured in a microtitre plate reader
(VICTOR
3 , Perkin Elmer). The positive control consists of wells that contain solvent 30 (0.5 % DMSO in test buffer) and display uninhibited kinase activity. Wells that contain test buffer instead of enzyme act as a control for the background kinase activity. -66- WO 2011/039344 PCT/EP2010/064628 The IC50 values are determined from concentration-activity analyses by iterative calculation using a sigmoid curve analysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a variable Hill coefficient. 5 Table 2 that follows lists the IC50 values of the example compounds 1 - 111 as obtained by determining from Assay 1 or Assay 2 (*). The inhibitory effect of compounds according to the invention is sufficiently demonstrated thereby. Table 2 PTK2 1 h PTK2 1 h PTK2 1 h No. IC [nM] No. IC [nM] No. IC 5 0 [nM] 1 6 23 3 45 5 2 5 24 1 46 34 3 3 25 2 47 3 4 5 26 1 48 22 5 4 27 1 49 5 6 17 28 2 50 4 7 8 29 3 51 13 8 4 30 1 52 6 9 19 31 3 53 4 10 7 32 400 54 92 11 7 33 7 55 6 12 4 34 2 56 9 13 4 35 2 57 2 14 3 36 3 58 6 15 11 37 28 59 6 16 4 38 1 60 3 17 13 39 6 61 4 18 4 40 3 62 3 19 4 41 2 63 3 20 3 42 4 64 6 21 12 43 22 65 10 22 8 44 6 66 16 -67- WO 2011/039344 PCT/EP2010/064628 No PTK2 1 h No PTK2 1 h No PTK2 1 h No IC. [nM] No IC [nM] N IC 5 0 [nM] 67 16 82 0.38 97 2 68 2 83 1 98 4 69 42 84 0.32 99 0.37 70 238 85 0.37 100 0.26 71 17 86 0.45 101 0.3 72 174 87 0.28 102 0.61 73 2 88 0.37 103 0.28 74 0.42 89 0.33 104 0.32 75 0.31 90 0.85* 105 0.39 76 0.29 91 4 106 1 77 0.3 92 3 107 103 78 0.37 93 0.42 108 0.44 79 0.4* 94 5 109 0.35 80 0.41 95 0.56 110 0.35 81 0.31 96 0.54 111 0.36 Soft-Agar Assay This cellular test is used to determine the influence of PTK2-inhibitors on the growth of PC-3 prostate carcinoma cells in soft agar ('anchorage-independent growth'). After an 5 incubation time of two weeks the cell vitality is demonstrated by Alamar Blue (resazurin) staining. PC-3 cells (ATCC CRL-1 435) are grown in cell culture flasks (175 cm 2 ) with F12 Kaighn's Medium (Gibco, No.: 21127) which has been supplemented with 10 % foetal calf serum 10 (Invitrogen, No.: 16000-044). The cultures are incubated in the incubator at 37'C and 5 % C02 and are passaged twice a week. The test is carried out in microtitre plates (Greiner, No.: 655 185) and consists of a lower layer made up of 90 pL of medium with 1.2 % agarose (Invitrogen, 4 % agarose gel lx liquid 40 mL, No.: 18300-012), followed by a cell layer in 60 pL medium and 0.3 % agarose and finally a top layer comprising 30 pL 15 medium which contains the test compounds (without the addition of agarose). To prepare the lower layer, 4 % agarose are decocted with lOx D-PBS (Gibco, No.: 14200) and H 2 0 and thus prediluted on 3 % agarose in 1 x D-PBS. The latter is adjusted with culture -68- WO 2011/039344 PCT/EP2010/064628 medium (F12 Kaighn's /10 % FCS) and FCS to a final dilution of 1.2 % agarose in F12 Kaighn's Medium with 10 % FCS. Each well of a microtitre plate is supplied with 90 pL of the suspension for the lower layer and cooled to RT for 1 h. For the cell layer, PC-3 cells are detached using trypsin (Gibco, 0.05 %; No.: 25300), counted and seeded in 60 pL F12 5 Kaighn's (10 % FCS) with the addition of 0.3 % agarose (37'C). After cooling to RT for 1 h the test compounds (30 pL from serial dilutions) are added for quadruple measurements. The concentration of the test compounds usually covers a test range of between 10 pM and 0.3 nM. The compounds (stock solution: 10 mM in 100 % DMSO) are prediluted in F12 Kaighn's Medium + 6% DMSO, to obtain a final concentration of 1 % 10 DMSO. The cells are incubated at 37'C and 5 % C02 in a steam-saturated atmosphere for 14 days. The metabolic activity of living cells is then demonstrated with the dye Alamar Blue (AbD Serotec, No.: BUFO12B). To do this, 18 pL/well of an Alamar Blue suspension are added and the whole is incubated for approx. 8 h in the incubator at 37'C. The positive control consists of empty wells that are filled with a mixture of 18 pL of 15 Alamar Blue reduced by autoclaving and 180 pL of F12 Kaighn's Medium (10 % FCS). The fluorescence intensity is determined by means of a fluorescence spectrometer (SpectraMAX GeminiXS, Molecular Devices). The excitation wavelength is 530 nm, the emission wavelength is 590 nm. 20 The EC 50 values are determined from concentrations-activity analyses by iterative calculation using a sigmoid curve analysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a variable Hill coefficient. Phospho-PTK2 (pY397) Assay 25 This cellular test is used to determine the influence of PTK2-inhibitors on the state of the PTK2-phosphorylation at tyrosine 397 (pY397). PC-3 cells (prostate carcinoma, ATCC CRL-1435) are grown in cell culture flasks (175 cm 2 ) with F12 Kaighn's Medium (Gibco, No.: 21127) with the addition of 10 % foetal calf serum (Invitrogen, No.: 16000-044). The cultures are incubated in the incubator at 30 37 'C and 5 % C02 and passaged twice a week. For the test, 2 x 104 cells pro well/90 pL medium are plated out in 96-well microtitre plates (Costar, No.: 3598) and incubated overnight in the incubator at 37 'C and 5 % C02. The test compounds (10 pL from serial dilution) are added the next day. The concentration of the test compounds usually covers a range of 50 pM and 0.8 nM. The test compounds -69- WO 2011/039344 PCT/EP2010/064628 (stock solution: 10 mM in 100 % DMSO) are diluted in medium/medium 10% DMSO such that the final concentration is 1 % DMSO. The cells are then incubated in the incubator at 37 C and 5 % C02 for 2 h. Then the culture supernatant is removed and the cells are fixed with 150 pL 4 % formaldehyde in D-PBS for 20 min at RT. (The cell lawn is washed 5 five times with 200 pl of 0.1% Triton X-100 in D-PBS) for 5 min each time and then incubated for 90 min with blocking buffer (5 % skimmed milk powder (Maresi Fixmilch) in TBST (25 mM Tris/HCI, pH 8.0, 150 mM NaCl, 0.05 % Tween 20). The blocking buffer is replaced by 50 pL of the first antibody anti-phospho PTK2 [pY397] rabbit monoclonal (Invitrogen/Biosource, No.: 44-625G), which is diluted 1:200 in blocking buffer. For control 10 purposes, alternatively a PTK2 [total] antibody (clone 4.47 mouse monoclonal, Upstate, No.: 05-537), diluted 1:400 in blocking buffer is used. This incubation is carried out at 4'C overnight. Then the cell lawn is washed five times with 100 pl 0.1% Tween in D-PBS for 5 min in each case and 50 pL/well of second antibody are added. In order to detect bound phospho-PTK2 [pY397] antibody a goat-anti-rabbit antibody is used which is 15 coupled with horseradish peroxidase (Dako, No.: P0448; 1:500 dilution in blocking buffer). In order to detect bound PTK2 [total]-antibodies a rabbit-anti-mouse antibody is used, which is also coupled with horseradish peroxidase (Dako, No.: P0161; 1:1000 dilution in blocking buffer). This incubation is carried out for 1 h at RT with gentle shaking. The cell lawn is then again washed five times with 100 pl of 0.1% Tween in D-PBS for 5 min in 20 each case. Peroxidase staining is carried out by adding 100 pL staining solution (1:1 mixture of TMB peroxidase substrate (KPL, No.: 50-76-02) and peroxidase solution B
(H
2 0 2 ) (KPL, No.: 50-65-02). The development of the stain takes place for 10 to 30 min in the dark. The reaction is stopped by the addition of 100 pL/well of a 1 M phosphoric acid solution. The absorption is determined photometrically at 450 nm with an absorption 25 measuring device (VICTOR 3 PerkinElmer). The inhibition of the anti-phospho PTK2 [pY397] immune staining is used to determine EC 50 values. The staining with anti-PTK2 [total]-antibodies is for control purposes and should remain constant under the influence of inhibitor. The EC 50 values are determined from concentration-activity analyses by iterative 30 calculation with the aid of a sigmoid curve analysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a variable Hill coefficient. Example compounds 1 - 100 have an EC 50 value (PC-3) of less than 10 pM, generally less than 1 pM. -70- WO 2011/039344 PCT/EP2010/064628 The substances of the present invention are PTK2 kinase inhibitors. In view of their biological properties the new compounds of general formula (1a) or (1b), the isomers thereof and the physiologically acceptable salts thereof are suitable for the treatment of 5 diseases characterised by excessive or abnormal cell proliferation. Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; 10 leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g. endometrial hyperplasia)); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). 15 For example, the following cancers may be treated with compounds according to the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as fibrillary, 20 protoplasmic, gemistocytary, anaplastic, pilocytic astrocytomas, glioblastoma, gliosarcoma, pleomorphic xanthoastrocytoma, subependymal large-cell giant cell astrocytoma and desmoplastic infantile astrocytoma; brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, hypophyseal incidentaloma, HGH (human growth hormone) producing adenoma and corticotrophic adenoma, craniopharyngiomas, 25 medulloblastoma, meningeoma and oligodendroglioma; nerve tumours such as for example tumours of the vegetative nervous system such as neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant 30 Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon, anus and duodenum; eyelid tumours (basalioma or adenocarcinoma of the eyelid apparatus); retinoblastoma; carcinoma of the pancreas; carcinoma of the bladder; lung tumours (bronchial carcinoma - small-cell lung cancer (SCLC), non-small-cell lung cancer -71- WO 2011/039344 PCT/EP2010/064628 (NSCLC) such as for example spindle-cell plate epithelial carcinomas, adenocarcinomas (acinary, paillary, bronchiolo-alveolar) and large-cell bronchial carcinoma (giant cell carcinoma, clear-cell carcinoma); breast cancer such as ductal, lobular, mucinous or tubular carcinoma, Paget's carcinoma; non-Hodgkin's lymphomas (B-lymphatic or T 5 lymphatic NHL) such as for example hair cell leukaemia, Burkitt's lymphoma or mucosis fungoides; Hodgkin's disease; uterine cancer (corpus carcinoma or endometrial carcinoma); CUP syndrome (Cancer of Unknown Primary); ovarian cancer (ovarian carcinoma - mucinous or serous cystoma, endometriodal tumours, clear cell tumour, Brenner's tumour); gall bladder cancer; bile duct cancer such as for example Klatskin 10 tumour; testicular cancer (germinal or non-germinal germ cell tumours); laryngeal cancer such as for example supra-glottal, glottal and subglottal tumours of the vocal cords; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, chondrosarcoma, osteoma, osteoid osteoma, osteoblastoma, osteosarcoma, non-ossifying bone fibroma, osteofibroma, desmoplastic bone fibroma, 15 bone fibrosarcoma, malignant fibrous histiocyoma, osteoclastoma or giant cell tumour, Ewing's sarcoma, and plasmocytoma, head and neck tumours (HNO tumours) such as for example tumours of the lips, and oral cavity (carcinoma of the lips, tongue, oral cavity), nasopharyngeal carcinoma (tumours of the nose, lymphoepithelioma), pharyngeal carcinoma, oropharyngeal carcinomas, carcinomas of the tonsils (tonsil malignoma) and 20 (base of the) tongue, hypopharyngeal carcinoma, laryngeal carcinoma (cancer of the larynx), tumours of the paranasal sinuses and nasal cavity, tumours of the salivary glands and ears; liver cell carcinoma (hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia 25 (CML); stomach cancer (papillary, tubular or mucinous adenocarcinoma, adenosquamous, squamous or undifferentiated carcinoma); malignant melanomas such as for example superficially spreading (SSM), nodular (NMM), lentigo-maligna (LMM), acral-lentiginous (ALM) or amelanotic melanoma (AMM); renal cancer such as for example kidney cell carcinoma (hypernephroma or Grawitz's tumour); oesophageal 30 cancer; penile cancer; prostate cancer; vaginal tumors (vaginal carcinoma or cervical carcinoma); thyroid carcinomas such as for example papillary, follicular, medullary or anaplastic thyroid carcinoma; thymus carcinoma (thymoma); cancer of the urethra (carcinoma of the urethra, urothelial carcinoma) and vulvar carcinoma. -72- WO 2011/039344 PCT/EP2010/064628 The new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other "state-of-the-art" compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies. 5 The compounds of general formula (1a) and (1b) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances. 10 Chemotherapeutic agents which may be administered in combination with the compounds according to the invention include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, 15 medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example "platelet derived growth factor" and "hepatocyte growth factor", inhibitors are for example "growth factor" antibodies, "growth factor receptor" antibodies and tyrosinekinase 20 inhibitors, such as for example gefitinib, lapatinib and trastuzumab); signal transduction inhibitors (e.g. Imatinib and sorafenib); antimetabolites (e.g. antifolates such as methotrexate, premetrexed and raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics 25 (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, 30 thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon -73- WO 2011/039344 PCT/EP2010/064628 alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer. Other possible combination partners are 2-chlorodesoxyadenosine, 2-fluorodesoxy cytidine, 2-methoxyoestradiol, 2C4, 3-alethin, 131-1-TM-601, 3CPA, 7-ethyl-10 5 hydroxycamptothecin, 16-azaepothilon B, A 105972, A 204197, aldesleukin, alitretinoin, altretamin, alvocidib, amonafid, anthrapyrazole, AG-2037, AP-5280, apaziquon, apomin, aranose, arglabin, arzoxifen, atamestan, atrasentan, auristatin PE, AVLB, AZ1 0992, ABX E G F, AR RY-300, ARRY-142886/AZD-6244, ARRY-704/AZD-8330, AS-703026, azacytidin, azaepothilon B, azonafid, BAY-43-9006, BBR-3464, BBR-3576, bevacizurmab, 10 biricodar dicitrate, BCX-1 777, bleocin, BLP-25, BMS-1 84476, BMS-247550, BMS-1 88797, BMS-275291, BNP-1350, BNP-7787, BIBW 2992, BIBF 1120, bleomycinic acid, bleomycin A, bleomycin B, bryostatin-1, bortezomib, brostallicin, busulphan, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamid, capecitabin, carboxyphthalatoplatin, CCI-779, CEP-701, CEP-751, CBT-1cefixim, ceflatonin, 15 ceftriaxon, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisen, cilengitid, ciclosporin, CDA-II, CDC-394, CKD-602, clofarabin, colchicin, combretastatin A4, CHS-828, CLL-Thera, CMT-3cryptophycin 52, CTP-37, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabin, D 24851, decitabin, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptid, desoxyepothilon B, dexamethasone, dexrazoxanet, 20 diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, E7010, E-6201, edatrexat, edotreotid, efaproxiral, eflornithin, EKB-569, EKB-509, elsamitrucin, epothilon B, epratuzumab, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidin, ethynyloestradiol, exatecan, exatecan mesylate, exemestan, exisulind, fenretinid, floxuridin, folic acid, FOLFOX, FOLFIRI, formestan, galarubicin, gallium maltolate, gefinitib, gemtuzumab, 25 gimatecan, glufosfamid, GCS-lOO, G17DT immunogen, GMK, GPX-1 00, GSK-5126766, GSK-1 120212, GW2016, granisetron, hexamethylmelaminr, histamine, homoharringtonin, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronat, ibritumomab, idatrexat, idenestrol, IDN-5109, IMC-1C11, immunol, indisulam, interferon alpha-2a, interferon alfa-2b, interleukin-2, ionafarnib, iproplatin, irofulven, isohomohalichondrin-B, 30 isoflavone, isotretinoin, ixabepilon, JRX-2, JSF-154, J-107088, conjugated oestrogens, Kahalid F, ketoconazole, KW-2170, lobaplatin, leflunomid, lenograstim, leuprolid, leuporelin, lexidronam, LGD-1550, linezolid, lutetium-texaphyrin, lometrexol, losoxantron, LU 223651, lurtotecan, mafosfamid, marimastat, mechloroethamin, methyltestosterone, -74- WO 2011/039344 PCT/EP2010/064628 methylprednisolone, MEN-10755, MDX-H210, MDX-447, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MLN518, motexafin-gadolinium, MS-209, MS-275, MX6, neridronat, neovastat, nimesulid, nitroglycerine, nolatrexed, norelin, N acetylcysteine, 06-benzylguanine, omeprazole, oncophage, ormiplatin, ortataxel, 5 oxantrazole, oestrogen, patupilon, pegfilgrastim, PCK-3145, PEG-filgrastim, PBI-1402, PEG-paclitaxel, PEP-005, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosin, perillylalcohol, P G-TXL, PG2, PLX-4032/RO-5185426, PT-100, picoplatin, pivaloyloxymethylbutyrate, pixantron, phenoxodiol 0, PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, RAF-265, 10 ramosetron, ranpirnase, RDEA-119/BAY 869766, rebeccamycin analogues, revimid, RG 7167, rhizoxin, rhu-mab, risedronat, rituximab, rofecoxib, Ro-31-7453, RO-5126766, RPR 109881A, rubidazon, rubitecan, R-flurbiprofen, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SRL-172, sorafenib, spiroplatin, squalamin, 15 suberanilohydroxamic acid, sutent, T 900607, T 138067, TAS-103, tacedinalin, talaporfin, tariquitar, taxotere, taxoprexin, tazaroten, tegafur, temozolamid, tesmilifen, testosterone, testosterone propionate, tetraplatin, tetrodotoxin, tezacitabin, thalidomide, theralux, therarubicin, thymectacin, tiazofurin, tipifarnib, tirapazamin, tocladesin, tomudex, toremofin, trabectedin, transMID-107, transretino i c acid, traszutumab, tretinoin, 20 triacetyluridine, triapin, trimetrexate, TLK-286TXD 258, urocidin, valrubicin, vatalanib, vincristin, vinflunin, virulizin, WX-UK1, vectibix, xeloda, XELOX, XL-281, XL-518/R-7420, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, zoledronate and zosuquidar. 25 Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infusion - syrups, elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. In amounts which are sufficient to achieve the dosage range specified below. 30 The doses specified may, if necessary, be given several times a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium -75- WO 2011/039344 PCT/EP2010/064628 phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. 5 Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the 10 tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, 15 glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. 20 Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection 25 vials or ampoules or infusion bottles. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. 30 Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. -76- WO 2011/039344 PCT/EP2010/064628 Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic 5 mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). 10 The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as 15 magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above. 20 For parenteral use, solutions of the active substances with suitable liquid carriers may be used. The dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour. 25 However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum 30 dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day. -77- WO 2011/039344 PCT/EP2010/064628 The formulation examples that follow illustrate the present invention without restricting its scope: Examples of pharmaceutical formulations 5 A) Tablets per tablet active substance according to formula (1a)(1b) 100 mg lactose 140 mg 10 corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg 15 The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is 20 compressed to produce tablets of suitable shape and size. B) Tablets per tablet active substance according to formula (1a)(1b) 80 mg 25 lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg 30 magnesium stearate 2 mg 400 mg -78- WO 2011/039344 PCT/EP2010/064628 The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in 5 and the mixture is compressed to form tablets of a suitable size. C) Ampoule solution active substance according to formula (1a)(1b) 50 mg 10 sodium chloride 50 mg water for inj. 5 mL The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from 15 pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. -79-

Claims (11)

1. Compounds of general formula (1a) and (1b) R IR 3 R IR 3 N ( R 4) N-! N (q R 5 ) H N, R2 HN ,R2 (1a) (1 b) wherein 5 A denotes a group, optionally substituted by one or more, identical or different R 2 , selected from among C 3 - 1 ocycloalkyl, 3-8 membered heterocycloalkyl, C 6 . 1 5 aryl and 5-12 membered heteroaryl; Q denotes a group, optionally substituted by one or more, identical or different R 4 , selected from among phenyl and 5-6 membered heteroaryl; 10 R 1 denotes a group selected from among halogen, -ORc, -OCF 3 , -SRc, -NRcRc, -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , C 1 - 3 alkyl, C 1 - 3 haloalkyl and C 1 - 3 haloalkyloxy; R 2 , R 4 and R 5 each independently of one another denote hydrogen or a group selected from among Ra, Rb and Ra substituted by one or more, identical or different Rc and/or Rb; R 3 denotes a group selected from among -OS(O)Rc, -OS(O) 2 Rc, -OS(O) 2 ORc, 15 -OS(O)NRcRc, -OS(O) 2 NRcRc, -OC(O)Rc, -OC(O)ORc, -OC(O)SRc, -OC(O)NRcRc, -SC(O)Rc, -SC(O)ORc, -SC(O)NRcRc, -N(Rg)C(O)Rc, -N[C(O)Rc]2, -N(OR9)C(O)Rc, -N[C(O)Rc]NRcRc, -N(Rg)S(O)Rc, -N(Rg)S(O)ORc, -N(Rg)S(O)2Rc, -N[S(O)2Rc]2 -N(Rg)S(O)2ORc, -N(Rg)S(O)2NRcRc, -N(Rg)[S(O)2]2Rc, -N(Rg)C(O)ORc, -N(Rg)C(O)SRc, -N(Rg)C(O)NRcRc, -N(Rg)C(O)NRgNRcRc, -[N(Rg)C(O)]2Rc, -N(Rg)[C(O)]2Rc, -N{[C(O)]2Rcj2 20 -N(Rg)[C(O)]2ORc, -N(Rg)[C(O)]2NRcRc, -N{[C(O)] 2 ORc} 2 , -N{[C(O)] 2 NRcRc} 2 and -[N(Rg)C(O)]2ORc; each Ra is independently selected from among C1. 6 alkyl, C3- 1 ocycloalkyl, C4. 16 cycloalkylalkyl, C 6 . 1 0 aryl, C 716 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered -80- WO 2011/039344 PCT/EP2010/064628 heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and
6-18 membered heteroarylalkyl; each Rb is a suitable group and each is independently selected from among =0, -ORc, C 1 - 3 haloalkyloxy, -OCF 3 , =S, -SRc, =NRc, =NORc, =NNRRc, =NN(Rg)C(O)NRcRc, -NRcRc, 5 -ONRcRc, -N(ORc)Rc, -N(Rg)NRcRc, halogen, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)Rc, -S(O)ORc, -S(O) 2 Rc, -S(O) 2 ORc, -S(O)NRcRc, -S(O) 2 NRcRc, -OS(O)Rc, -OS(O) 2 Rc, -OS(O) 2 ORc, -OS(O)NRcRc, -OS(O) 2 NRcRc, -C(O)Rc, -C(O)ORc, -C(O)SRc, -C(O)NRcRc, -C(O)N(Rg)NRcRc, -C(O)N(Rg)ORc, -C(NR9)NRcRc, -C(NOH)Rc, -C(NOH)NRcRc, -OC(O)Rc, -OC(O)ORc, -OC(O)SRc, -OC(O)NRcRc, -OC(NR9)NRcRc, 10 -SC(O)Rc, -SC(O)ORc, -SC(O)NRcRc, -SC(NR9)NRcRc, -N(Rg)C(O)Rc, -N[C(O)RC]2 -N(OR9)C(O)Rc, -N(Rg)C(NR9)Rc, -N(Rg)N(Rg)C(O)Rc, -N[C(O)Rc]NRcRc, -N(Rg)C(S)Rc, -N(Rg)S(O)Rc, -N(Rg)S(O)ORc, -N(Rg)S(O)2Rc, -N[S(O)2RC]2, -N(Rg)S(O)2ORc, -N(Rg)S(O)2NRcRc, -N(Rg)[S(O)2]2Rc, -N(Rg)C(O)ORc, -N(Rg)C(O)SRc, -N(Rg)C(O)NRcRc, -N(Rg)C(O)NRgNRcRc, -N(Rg)N(Rg)C(O)NRcRc, -N(Rg)C(S)NRcRc, -[N(Rg)C(O)]2Rc, 15 -N(Rg)[C(O)]2Rc, -N{[C(O)]2RE}2, -N(Rg)[C(O)]2ORc, -N(Rg)[C(O)]2NRcRc, -N{[C(O)]2ORCj2 -N{[C(O)]2NRcRE}2, -[N(Rg)C(O)]2ORc, -N(Rg)C(NR9)ORc, -N(Rg)C(NOH)Rc, -N(Rg)C(NR9)SRc and -N(Rg)C(NR9)NRcRc; each RC independently denotes hydrogen or a group optionally substituted by one or more, identical or different Rd and/or R* selected from among C1. 6 alkyl, C3- 1 ocycloalkyl, 20 C4 11 cycloalkylalkyl, C 6 . 1 0 aryl, C 7 16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl; each Rd is a suitable group and each is independently selected from among =0, -ORe, C 1 - 3 haloalkyloxy, -OCF 3 , =S, -SRe, =NRe, =NORe, =NNReRe, =NN(Rg)C(O)NRR, -NReRe, 25 -ONReRe, -N(Rg)NReRe, halogen, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)Re, -S(O)ORe, -S(O) 2 Re, -S(O) 2 ORe, -S(O)NReRe, -S(O) 2 NReRe, -OS(O)Re, -OS(O) 2 R*, -OS(O) 2 ORe, -OS(O)NReRe, -OS(O) 2 NReRe, -C(O)Re, -C(O)ORe, -C(O)SRe, -C(O)NReRe, -C(O)N(Rg)NReRe, -C(O)N(Rg)ORe, -C(NR9)NReRe, -C(NOH)Re, -C(NOH)NReRe, -OC(O)Re, -OC(O)ORe, -OC(O)SRe, -OC(O)NReRe, -OC(NR9)NReR, 30 -SC(O)Re, -SC(O)ORe, -SC(O)NReRe, -SC(NR)NReRe, -N(Rg)C(O)Re, -N[C(O)Re -N(OR9)C(O)Re, -N(Rg)C(NR9)Re, -N(Rg)N(Rg)C(O)Re, -N[C(O)Re]NReRe, -N(Rg)C(S)Re, -N(Rg)S(O)Re, -N(Rg)S(O)ORe, -N(Rg)S(O)2Re, -N[S(O)2Re]2, -N(Rg)S(O)2ORe, -81- WO 2011/039344 PCT/EP2010/064628 -N(Rg)S(O)2NR*Re, -N(Rg)[S(O)2]2Re, -N(Rg)C(O)ORe, -N(Rg)C(O)SRe, -N(Rg)C(O)NReRe, -N(Rg)C(O)NRgNR*Re, -N(Rg)N(Rg)C(O)NReRe, -N(Rg)C(S)NReRe, -[N(Rg)C(O)]2Re, -N(Rg)[C(O)]2Re, -N{[C(O)]2Re}2, -N(Rg)[C(O)]2ORe, -N(Rg)[C(O)]2NR*Re, -N{[C(O)]2ORe12 -N{[C(O)] 2 NRRe} 2 , -[N(Rg)C(O)]2ORe, -N(Rg)C(NRg)ORe, -N(Rg)C(NOH)Re, 5 -N(Rg)C(NR9)SRe and -N(Rg)C(NR9)NReRe; each R* independently denotes hydrogen or a group optionally substituted by one or more, identical or different Rf and/or R9 selected from among C 1 . 6 alkyl, C 3 - 8 cycloalkyl, C 4 . 11 cycloalkylalkyl, C 6 . 1 oaryl, C 7 . 16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 10 6-18 membered heteroarylalkyl; each Rf is a suitable group and each is independently selected from among halogen and -CF 3 ; each R9 independently denotes hydrogen, C 1 . 6 alkyl, C 3 - 8 cycloalkyl, C 4 . 11 cycloalkylalkyl, C 6 . 1 oaryl, C 7 . 1 6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 15 membered heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered heteroarylalkyl; m and p independently of one another denote 0, 1, 2 or 3 and n and q denote 0, 1, 2 or 3; optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers 20 and the mixtures thereof, and optionally the salts thereof, particularly the pharmacologically acceptable acid addition salts thereof. 2. Compounds of general formula (1a) according to claim 1 R IR3 N z!,N ( (R 4 )m H N, R 2 (1a) -82- WO 2011/039344 PCT/EP2010/064628 wherein R', R 2 , R 3 , R 4 , A, Q, n and m are defined as in claim 1. 3. Compounds according to claim 2, wherein n is 1. 5 4. Compounds according to one of claims 1 to 3, wherein m is equal to 0. 5. Compounds of general formula (1 b) according to claim 1 R IR3 N-. N q (R HN& R2 (1 b) wherein 10 R', R 2 , R 3 , R 5 , A, p and q are defined as in claim 1. 6. Compounds according to claim 5, wherein q is equal to 1 or 2.
7. Compounds according to one of claims 5 or 6, wherein p is equal to 0. 15 8. Compounds according to one of claims 1 to 7, wherein R 3 is selected from among -N(Rg)C(O)Rc, -N(OR9)C(O)Rc, -N(Rg)S(O)2Rc, -N(Rg)C(O)ORc and -N(Rg)C(O)NRcRc and -83- WO 2011/039344 PCT/EP2010/064628 RC and RI are defined as in claim 1.
9. Compounds according to one of claims 1 to 8, wherein the group R 2 ,Q R 5 denotes (R 7 )r R 6 R 6 and R 7 are defined as R 2 in claim 1, r is equal to 1 or 2 and A is defined as in claim 1. 10 10. Compounds according to claim 9, wherein A is a group selected from among phenyl and 5-10 membered heteroaryl and R 6 , R 7 and r are defined as in claim 9.
11. Compounds according to claim 10, wherein A is a phenyl; 15 r has the value 1 or 2; each R 7 is independently selected from among halogen, C 1 . 6 alkyl and C 1 . 6 alkoxy and R 6 is defined as in claim 9.
12. Compounds according to one of claims 9 to 11, wherein R 6 is selected from among hydrogen, Ra2, Rb 2 and Ra 2 substituted by one or more, 20 identical or different Rb 2 and/or Rc 2 ; -84- WO 2011/039344 PCT/EP2010/064628 each Ra 2 is independently selected from among C 1 . 6 alkyl and 3-7 membered heterocycloalkyl; each Rb 2 is a suitable substituent and is independently selected from among O=, -ORc 2 -NR c2 Rc2, -C(O)R c2, -C(O)OR c2, -C(O)NR c2 Rc2, -C(O)N(R g2 )OR c2, -N(R g2)C(O )R c2 5 -N(Rg2)C(O)ORc2 and -N(Rg2)C(O)NRc2Rc2 each Rc 2 independently denotes hydrogen or a group optionally substituted by one or more, identical or different Rd 2 and/or Re 2 , selected from among C 1 . 6 alkyl, C 3 - 6 cycloalkyl and 3-7 membered heterocycloalkyl; each Rd 2 is a suitable substituent and is independently selected from among -ORe 2 10 -NRe 2 Re 2 , -C(O)N(Rg2)ORe2 and -C(O)NRe 2 Re 2 ; each Re 2 independently denotes hydrogen or a group optionally substituted by one or more, identical or different Ru and/or R2, selected from among C 1 . 6 alkyl, C 3 - 6 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl; each Rf 2 independently denotes -ORg2 and 15 each Rg2 is independently selected from among hydrogen, C 1 . 6 alkyl and C 4 .gcycloalkylalkyl.
13. Compounds according to claim 1 selected from among 23 4-[4-((1 R,2R)-1 -methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin 2-ylamino]-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 24 2-fluoro-4-[4-((1 R,2R)-1 -methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl pyrimidin-2-ylamino]-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 25 2-fluoro-4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 27 4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-3-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 28 2-fluoro-4-[4-((1 R,2R)-2-methanesulphonylamino-cyclopentyloxy)-5-trifluoromethyl pyrimidin-2-ylamino]-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 29 4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-3-methoxy-N-((3S,4S)-3-methoxy-1 -methyl-piperidin-4-yl) -85- WO 2011/039344 PCT/EP2010/064628 benzamide 31 2-fluoro-4-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-((3S,4S)-3-methoxy-1 -methyl piperidin-4-yl)-benzamide 74 2-chloro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 75 2-fluoro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 77 4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-3-methoxy-N-(4-methyl-piperazin-1 -yl)-benzamide 79 3-{4-[(1 R,2R)-1 -(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl pyrimidin-2-ylamino}-4-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 84 2-chloro-4-{5-chloro-4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino) cyclopentyloxy]-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 85 4-{5-chloro-4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy] pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide 88 4-{5-chloro-4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy] pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(4-methyl-piperazin-1 -yl)-benzamide 90 N-((1 R,2R)-2-{2-[4-(4-tert-butyl-piperazin-1 -yl)-2-methoxy-phenylamino]-5 trifluoromethyl-pyrimidin-4-yloxy}-indan-1 -yl)-N-methyl-methanesulphonamid 100 2-chloro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1 -yl) benzamide 101 2-fluoro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1 -yl) benzamide 102 2-chloro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 103 2-fluoro-4-{4-[(1 R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5 -86- WO 2011/039344 PCT/EP2010/064628 trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1 -methyl-piperidin-4-yl) benzamide 104 2-fluoro-4-[4-((1 R,2R)-2-methanesulphonylamino-cyclohexyloxy)-5-trifluoromethyl pyrimidin-2-ylamino]-5-methoxy-N-(1 -methyl-piperidin-4-yl)-benzamide
14. Compounds according to one of claims 1 to 13 - or the pharmaceutically acceptable salts thereof - as medicaments.
15. Compounds according to one of claims 1 to 13 - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prevention of cancer, infections, 5 inflammations and autoimmune diseases.
16. Pharmaceutical preparation containing as active substance one or more compounds according to one of claims 1 to 13 - or the pharmaceutically acceptable salts thereof- optionally in combination with conventional excipients and/or carriers.
17. Pharmaceutical preparation comprising a compound according to one of claims 1 10 to 13 - or one of the pharmaceutically acceptable salts thereof- and at least one other cytostatic or cytotoxic active substance different from (1a) and (1 b). -87-
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